US6867221B2 - Cyclic amine compounds and pharmaceutical composition containing the same - Google Patents

Cyclic amine compounds and pharmaceutical composition containing the same Download PDF

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Publication number
US6867221B2
US6867221B2 US10/191,534 US19153402A US6867221B2 US 6867221 B2 US6867221 B2 US 6867221B2 US 19153402 A US19153402 A US 19153402A US 6867221 B2 US6867221 B2 US 6867221B2
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Prior art keywords
trimethoxyphenyl
methyl
pyridin
substituted
piperidine
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US20040010147A1 (en
Inventor
Tatsuhiko Kodama
Masahiro Tamura
Toshiaki Oda
Yukiyoshi Yamazaki
Masahiro Nishikawa
Shunji Takemura
Takeshi Doi
Yoshinori Kyotani
Masao Ohkuchi
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Kowa Co Ltd
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Kowa Co Ltd
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Priority claimed from US09/941,684 external-priority patent/US6395753B1/en
Priority claimed from US10/107,180 external-priority patent/US6605620B1/en
Application filed by Kowa Co Ltd filed Critical Kowa Co Ltd
Priority to US10/191,534 priority Critical patent/US6867221B2/en
Priority to CNB028171403A priority patent/CN100406441C/en
Priority to PCT/JP2002/008650 priority patent/WO2003020703A1/en
Priority to CA2461963A priority patent/CA2461963C/en
Priority to HU0401733A priority patent/HUP0401733A3/en
Priority to RU2004109224/04A priority patent/RU2299207C2/en
Priority to EP02762881A priority patent/EP1422219A4/en
Priority to JP2003524974A priority patent/JP4276070B2/en
Priority to KR10-2004-7002264A priority patent/KR20040030114A/en
Priority to NZ531498A priority patent/NZ531498A/en
Priority to AU2002328576A priority patent/AU2002328576B8/en
Priority to TW091119680A priority patent/TWI254706B/en
Assigned to KOWA CO., LTD. reassignment KOWA CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DOI, TAKESHI, KODAMA, TATSUHIKO, KYOTANI, YOSHINORI, NISHIKAWA, MASAHIRO, ODA, TOSHIAKI, OHKUCHI, MASAO, TAKEMURA, SHUNJI, TAMURA, MASAHIRO, YAMAZAKI, YUKIYOSHI
Publication of US20040010147A1 publication Critical patent/US20040010147A1/en
Priority to NO20040877A priority patent/NO327074B1/en
Publication of US6867221B2 publication Critical patent/US6867221B2/en
Application granted granted Critical
Priority to HK05106102A priority patent/HK1073312A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to novel cyclic amine compounds which have inhibitory effects on both cell adhesion and cell infiltration and are useful as anti-asthmatic agents, anti-allergic agents, anti-rheumatic agents, anti-arteriosclerotic agents, anti-inflammatory agents, anti-Sjogren's syndrome agents or the like, and medicines containing such compounds.
  • Sjogren's syndrome in humans is an organ-specific autoimmune disease characterized by lymphocytic infiltration into the salivary and lacrimal glands, resulting in symptoms of dry mouth and dry eye due to insufficient secretion (Fox R I et al.: “Sjogren's syndrome: proposed criteria for classification” Arthritis Rheum., 29, 577-585(1986)).
  • cytokines Infiltration of these leukocytes is elicited by cytokines, chemokines, lipids, and complements produced in inflammatory sites (Albelda, S M. et al., FASEB J., , 504-512 (1994)).
  • Activated leukocytes adhere to vascular endothelial cells through an interaction called rolling or tethering with endothelial cells activated likewise. Thereafter, the leukocytes transmigrate through endothelium to infiltrate into the inflammatory sites (Springer, T A., Annu. Rev. Physiol., 57, 827-872 (1995)).
  • various cell adhesion molecules such as an immunoglobulin superfamily (ICAM-1, VCAM-1 and the like), a selectin family (E-selectin and the like), an integrin family (LFA-1, VLA-4 and the like) and CD44, which are induced on the surfaces of the cells by stimulation by cytokines or the like, play important roles (“Rinsho Meneki (Clinical Immune)”, 30, Supple. 18 (1998)), and a relationship between the disorder state and aberrant expression of the cell adhesion molecules is noted.
  • ICM-1 immunoglobulin superfamily
  • VCAM-1 a selectin family
  • E-selectin and the like an integrin family
  • LFA-1, VLA-4 and the like integrin family
  • CD44 CD44
  • an agent capable of inhibiting cell adhesion or cell infiltration can be useful as an agent for preventing and treating allergic diseases such as bronchial asthma, dermatitis, rhinitis and conjunctivitis; autoimmune diseases such as rheumatoid arthritis, nephritis, Sjogren's syndrome, inflammatory bowel diseases, diabetes and arteriosclerosis; and chronic inflammatory diseases.
  • allergic diseases such as bronchial asthma, dermatitis, rhinitis and conjunctivitis
  • autoimmune diseases such as rheumatoid arthritis, nephritis, Sjogren's syndrome, inflammatory bowel diseases, diabetes and arteriosclerosis
  • chronic inflammatory diseases such as chronic bronchial asthma, dermatitis, rhinitis and conjunctivitis.
  • an anti-VLA-4 antibody and an anti-CD44 antibody reduce the incidence of disease symptoms in a mouse collagen arthritis model (Zeidler, A. et al., Autoimmunity, 21, 245-252 (1995)). Even in cell adhesion molecule deficient-mice, inhibition of infiltration of leukocytes into inflammatory tissues is observed likewise in inflammatory models (Bendjelloul, F. et al., Clin. Exp. Immunol., 119, 57-63 (2000); Wolyniec, W W. et al., Am. J. Respir. Cell Mol. Biol., 18, 777-785 (1998); Bullard, D C. et al., J. Immunol., 157, 3153-3158 (1996)).
  • An object of the present invention is to provide a substance having inhibitory effects on both cell adhesion and cell infiltration, plus excellent anti-asthmatic effects, anti-allergic effects, anti-rheumatic effects, anti-arteriosclerotic effects, anti-inflammatory effects and anti-Sjogren's syndrome effect.
  • the present invention provides a cyclic amine compound represented by the following general formula (1): wherein,
  • a medicine comprising the above cyclic amine compound, a salt thereof, or a hydrate thereof as an active ingredient.
  • a pharmaceutical composition comprising the above cyclic amine compound, the salt thereof, or the hydrate thereof and a pharmaceutically acceptable carrier.
  • a method for treating a disease caused by cell adhesion and/or cell infiltration which comprises administering an effective amount of the above cyclic amine compound, a salt thereof, or a hydrate thereof to a patient who requires such treatment.
  • the compound of the present invention is characterized in that the cyclic amine has two phenyl-pyridyl or biphenyl groups, or phenyl-pyridyl and biphenyl groups. It has not been known at all that compounds having such structure have both of excellent cell adhesion-inhibiting effects and cell infiltration-inhibiting effects.
  • the halogen atoms for R 1 , R 2 and R 3 include fluorine, chlorine, bromine and iodine atoms.
  • the alkyl group for R 1 , R 2 , R 3 and R 4 typically includes straight, branched or cyclic C 1 -C 8 alkyl groups, such as straight or branched C 1 -C 8 alkyl groups, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl groups, and C 3 -C 8 cycloalkyl groups, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl and cyclohexylethyl groups.
  • C 1 -C 6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like.
  • the halogen-substituted alkyl group for R 1 , R 2 and R 3 typically includes C 1 -C 8 alkyl groups substituted with 1 to 3 halogen atoms. Among them, particularly preferred are C 1 -C 6 alkyl groups substituted with 1 to 3 halogen atoms, such as trifluoromethyl, 2,2,2-trifluoroethyl, etc.
  • the alkoxy group typically includes straight, branched or cyclic C 1 -C 8 alkoxy groups, such as straight or branched C 1 -C 8 alkoxy groups, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy and hexyloxy groups; and C 3 -C 8 cycloalkyloxy groups, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxyl, cyclohexylmethyloxy and cyclohexylethyloxy groups.
  • C 1 -C 6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy and n-butyloxy groups.
  • the alkylthio group typically includes C 1 -C 8 alkylthio groups, and is preferably a C 1 -C 6 alkylthio group such as, for example, methylthio, ethylthio, n-propylthio, isopropylthio or the like.
  • the alkoxycarbonyl group typically includes C 1 -C 6 alkoxycarbonyl groups, and is preferably a C 1 -C 6 alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or the like.
  • the alkanoyl group typically includes C 1 -C 6 alkanoyl groups and is preferably a C 1 -C 4 alkanoyl group such as acetyl, propionyl, butyryl, isobutyryl or the like.
  • the alkenyl group for R 4 typically includes C 3 -C 8 alkenyl groups and is preferably a C 3 -C 6 alkenyl group such as 2-propenyl, 3-butenyl or the like.
  • the alkynyl group typically includes C 3 -C 8 alkynyl groups and is preferably a C 3 -C 6 alkynyl group such as 2-propynyl, 3-butynyl or the like.
  • the aryl group for R 4 typically includes C 6 -C 14 aryl groups and is preferably phenyl, naphthyl, anthryl, indenyl, indanyl, 5,6,7,8-tetrahydronaphthyl or the like.
  • the heteroaryl group for R 4 typically includes heteroaryl groups of 5- or 6-membered ring containing 1 to 4 nitrogen atoms in the ring, and is preferably imidazolyl, pyridyl, pyrimidinyl or the like.
  • the aralkyl group typically includes C 6 -C 14 aryl-C 1 -C 6 alkyl groups such as phenyl C 1 -C 6 alkyl groups and naphthyl C 1 -C 6 alkyl groups, for example, benzyl, naphthylmethyl, phenylethyl, phenylpropyl, etc.
  • the heteroaralkyl group typically includes 5- or 6-membered ring heteroaryl containing 1 to 4 nitrogen atoms-C 1 -C 6 alkyl groups, such as imidazolyl-C 1 -C 6 alkyl, pyridyl-C 1 -C 6 alkyl, pyrimidinyl-C 1 -C 6 alkyl, etc.
  • the groups which can substitute the above-mentioned aryl, heteroaryl, aralkyl and heteroaralkyl include 1 to 3 groups or atoms selected from alkyl, alkoxy, halogen-substituted alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halogen, nitro, amino, acetylamino, trifluoromethyl and alkylenedioxy, wherein said alkyl, alkoxy and alkylthio include those illustrated for R 1 ⁇ R 3 .
  • the alkyl group of the alkylsulfinyl group and alkylsulfonyl group typically includes C 1 -C 3 alkyl groups such as methyl, ethyl, n-propyl and isopropyl groups.
  • the halogen-substituted alkoxy includes C 1 -C 8 alkoxy groups substituted by 1 to 3 halogen atoms, and is preferably a C 1 -C 6 alkoxy group substituted by 1 to 3 halogen atoms such as trifluoromethoxy or 2,2,2-trifluoroethoxy.
  • the alkylenedioxy group typically includes C 1 -C 3 alkylenedioxy groups such as methylenedioxy, ethylenedioxy and propylenedioxy groups.
  • X represents NR 4 . More preferably, X represents NR 4 and R 4 represents a substituted or unsubstituted C 6 -C 14 aryl group or a substituted or unsubstituted 5- or 6-membered ring heteroaryl group containing 1 to 4 nitrogen atoms in the ring.
  • the compounds of the formula (1) wherein X represents NR 4 have particularly strong cell adhesion-inhibiting action as shown later in Test Example 1.
  • R 1 , R 2 and R 3 are attached to the phenyl group at the 3, 4 and 5-positions thereof.
  • R 1 and R 3 are an alkoxy group or a halogen.
  • R 2 is a hydrogen atom, a halogen atom, or a hydroxy, alkyl, halogen-substituted alkyl, alkoxy, alkylthio, carboxy, alkoxycarbonyl or alkanoyl group.
  • l denotes 0 or 1, and is preferably 1.
  • W 1 represents N.
  • W 2 represents N.
  • Most preferable compounds include the compounds of the formula (1), wherein X represents NR 4 , and R 4 represents a substituted or unsubstituted C 6 -C 14 aryl group or a substituted or unsubstituted 5- or 6-membered ring heteroaryl group containing 1 to 4 nitrogen atoms in the ring. Particularly preferably, R 4 represents a phenyl or pyridyl group which may be substituted with one or two groups or atoms selected from halogen, alkyl, alkoxy, alkylthio, trifluoromethyl and alkylenedioxy.
  • salts of the compounds (1) according to the invention are pharmaceutically acceptable salts.
  • examples include the acid-addition salts of mineral acids, such as hydrochlorides, hydrobromides, hydroiodides, sulfates and phosphates; and acid-addition salts of organic acids, such as benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, oxalates, maleates, fumarates, tartrates, citrates and acetates.
  • mineral acids such as hydrochlorides, hydrobromides, hydroiodides, sulfates and phosphates
  • organic acids such as benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, oxalates, maleates, fumarates, tartrates, cit
  • the compounds of formula (1) may be present in the form of solvates typified by hydrates, and the solvates are embraced in the present invention.
  • the compounds of formula (1) can be prepared in accordance with the following processes A ⁇ L:
  • compound (2) is reacted with ethyl isonipecotate (7) in a solvent such as acetonitrile, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dioxane, toluene, benzene, etc. in the presence of a base such as potassium carbonate or the like at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature overnight, to give compound (8).
  • a base such as potassium carbonate or the like
  • the compound (8) is subjected to a usual alkaline hydrolysis to give the corresponding carboxylic acid compound (9).
  • the carboxylic acid compound (9) is reacted with the amine compound (5) using a dehydration condensing agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (water-soluble carbodiimide), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) or the like in a solvent such as chloroform, dichloroethane, THF, dioxane, acetonitrile, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 12 hours, to give an end product (1A).
  • a dehydration condensing agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (water-soluble carbodiimide), 2-(1H-benzotriazol-1-
  • 4-hydroxypiperidine compound (10) with a protected amino group is reacted with compound (2) in the presence of sodium hydride or potassium iodide in a solvent such as DMF, DMSO, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 2 days, to give compound (11).
  • the protecting group in the compound (11) is removed in a known manner.
  • the resulting compound (12) is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give an end product (1B).
  • Isonipecotamide (13) is reacted with compound (2) in the presence of a base such as potassium carbonate, sodium carbonate or the like in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give compound (14).
  • a base such as potassium carbonate, sodium carbonate or the like
  • a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc.
  • the compound (14) is subjected to Hofmann rearrangement reaction to give amine compound (15).
  • the amine compound (15) mentioned in the above is reacted with 2-nitrobenzenesulfonyl chloride (19) according to a known manner to give compound (20).
  • the compound (20) is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane or the like at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give compound (21).
  • the compound (1D) is reacted with R 4 —B in the presence of a base such as sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate or the like in a solvent such as acetonitrile, THF, dioxane, chloroform, dichloromethane, DMF, DMSO or the like at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at 80° C. for 12 hours, to give compound (1D′).
  • a base such as sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate or the like
  • a solvent such as acetonitrile, THF, dioxane, chloroform, dichloromethane, DMF, DMSO or the like at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at 80° C. for 12 hours, to give compound (1D′).
  • a base such as potassium carbonate
  • a solvent such as acetonitrile, DMF, DMSO, THF, dioxane or the like
  • Aminopiperidine derivative (22) in which the amino group on the ring is protected is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane or the like at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give compound (23).
  • a base such as potassium carbonate
  • a solvent such as acetonitrile, DMF, DMSO, THF, dioxane or the like
  • the compound (23) is reacted with R 4 —B in the presence of a base such as sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate or the like in a solvent such as acetonitrile, THF, dioxane, chloroform, dichloroethane, DMF, DMSO or the like at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at 80° C. for 12 hours, to give compound (24).
  • a base such as sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate or the like
  • a solvent such as acetonitrile, THF, dioxane, chloroform, dichloroethane, DMF, DMSO or the like at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at 80° C. for 12 hours, to give compound (24).
  • the compound (25) is reacted compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane or the like at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give compound (1E).
  • a base such as potassium carbonate
  • a solvent such as acetonitrile, DMF, DMSO, THF, dioxane or the like at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give compound (1E).
  • 4-piperidone ethylene ketal (26) is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give compound (27), which in turn is deketalized by using an acid to give ketone compound (28).
  • a base such as potassium carbonate
  • a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc.
  • 4-piperidone (29) is reacted compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane or the like at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give compound (28).
  • a base such as potassium carbonate
  • a solvent such as acetonitrile, DMF, DMSO, THF, dioxane or the like
  • the resulting compound (30) is reacted compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give an end product (1F).
  • a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc.
  • 4-piperidone derivative (31) in which the amino group on the ring is protected is reacted with an amine compound R 4 —NH 2 similarly to the procedure for preparation of compound (30) in Process F to give compound (32).
  • the compound (32) is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give compound (33).
  • the resulting compound (34) is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give an end product (1G).
  • a base such as potassium carbonate
  • a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc.
  • 3-aminopyrrolidine derivative (35) with a protected amino group on the ring is reacted with 2-nitrobenzenesulfonyl chloride (19) under usual conditions to give a benzenesulfonyl derivative (36).
  • the derivative (36) is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give compound (37).
  • the protecting group of the amino group is removed from the compound (37) to give compound (38), which in turn is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give compound (39).
  • a base such as potassium carbonate
  • a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc.
  • Compound (36) is reacted with R 4 —B in the presence of a base such as sodium carbonate, potassium carbonate, etc. in a solvent such as acetonitrile, THF, dioxane, chloroform, dichloroethane, DMF, DMSO, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at 80° C. for 12 hours, to give compound (40).
  • the amino-protecting group is removed from the compound (40), and the resulting compound (41) is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc.
  • compound (42) By subjecting the compound (42) to a reaction similar to that in the preparation of compound (5) in Process A, compound (43) is obtained.
  • the compound (43) is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give an end product (1I).
  • a base such as potassium carbonate
  • a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc.
  • the compounds (1) according to the present invention are obtained by any of the above-described processes and may further be purified by using an ordinary purification means such as recrystallization or column chromatography as needed. As needed, the compounds may also be converted into the desired salts or solvates in a method known per se in the art.
  • the present invention includes any configurational isomers.
  • the compounds (1) according to the present invention, or salts or solvates thereof thus obtained have an excellent inhibitory effect on cell adhesion as demonstrated in the examples, which will be described subsequently, and are useful as medicines for treatment and prevention of diseases of animals including humans, caused by cell adhesion or cell infiltration, for example, asthma, allergy, rheumatism, arteriosclerosis, inflammation, Sjogren's syndrome, etc.
  • the medicine according to the present invention comprises a compound (1), a salt thereof, or a solvate thereof as an active ingredient.
  • the form of administration may be suitably selected as necessary for the therapeutic application intended without any particular limitation, including oral preparations, injections, suppositories, ointments, inhalants, eye drops, nose drops and plasters.
  • a composition suitable for use in these administration forms can be prepared by blending a pharmaceutically acceptable carrier in accordance with the conventional preparation method publicly known by those skilled in the art.
  • an excipient When an oral solid preparation is formulated, an excipient, and optionally, a binder, disintegrator, lubricant, colorant, a taste corrigent, a smell corrigent and the like are added to compound (1) and the resulting composition can be formulated into tablets, coated tablets, granules, powders, capsules, etc. in accordance with methods known in the art.
  • any additives may be used which are generally used in the pharmaceutical field.
  • excipients such as lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose and silicic acid
  • binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate and polyvinyl pyrrolidone
  • disintegrators such as dry starch, sodium alginate, agar powder, sodium hydrogencarbonate, calcium carbonate, sodium lauryl sulfate, monoglyceryl stearate and lactose
  • lubricants such as purified talc, stearic acid salts, borax and polyethylene glycol
  • taste corrigents such as sucrose, orange peel, citric acid and tartaric acid.
  • a taste corrigent, buffer, stabilizer, smell corrigent and/or the like are added to compound (1) and the resulting composition can be formulated into internal liquid preparations, syrup preparations, elixirs, etc. in accordance with methods known in the art.
  • vanillin as the taste corrigent may be used.
  • the buffer sodium citrate may be mentioned.
  • the stabilizer tragacanth, gum arabic and gelatin may be mentioned.
  • a pH adjustor, buffer, stabilizer, isotonicity agent, local anesthetic and the like may be added to compound (1) according to the present invention, and the resultant composition can be formulated into subcutaneous, intramuscular and intravenous injections in accordance with methods known in the art.
  • the pH adjustor and buffer in this case include sodium citrate, sodium acetate and sodium phosphate.
  • the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid and thiolactic acid.
  • the local anesthetic include procaine hydrochloride and lidocaine hydrochloride.
  • the isotonicity agent include sodium chloride and glucose.
  • a carrier preparation known in the art for example, polyethylene glycol, lanoline, cacao butter, fatty acid triglyceride or the like, and optionally, a surfactant such as Tween (trade mark) and the like are added to the compound (1), and the resultant composition can be formulated into suppositories in accordance with methods known in the art.
  • a base material When an ointment is formulated, a base material, stabilizer, wetting agent, preservative and the like, which are generally used, are blended with compound (1) as needed, and the resulting blend is mixed and formulated into ointments in accordance with known method known methods.
  • the base material include liquid paraffin, white vaseline, bleached beeswax, octyldodecyl alcohol and paraffin.
  • the preservative include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate and propyl p-hydroxybenzoate.
  • inhalants eye drops and nose drops may also be formulated in accordance with known methods.
  • the dose of the medicine according to the present invention varies according to the age, weight and condition of the patient to be treated, the administration method, the number of times of administration, and the like. It is however preferred that the medicine is generally orally or parenterally administered at once or in several portions in a dose of 1 to 1,000 mg per day in terms of compound (1), for an adult.
  • Ethyl 2-(3,4,5-trimethoxyphenyl)isonicotinate (24.57 g) was dissolved in dry THF (200 mL), and to the solution lithium aluminum hydride (2.94 g) was added at 0° C. under an argon atmosphere. The mixture was stirred at 0° C. for 1 hour as it is. A small amount of water and then sodium sulfate were added to the reaction mixture, and the reaction mixture was filtered through celite. The filtrate was evaporated, and the reultant crude crystals were recrystalized from ethyl acetate-hexane to give the title compound.
  • Piperidine-4-carboxamide (385 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (881 mg) were condensed by the same method as described in Example 2 to give the title compound as white needles.
  • Piperidine-4-carboxamide (301 mg) and 2-(4-chloro-3,5-dimethoxyphenyl)-4-chloromethylpyridine (600 mg) were coupled in the same manner as described in Example 2 to give the title compound.

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Abstract

A cyclic amine compound represented by the following general formula (1):
Figure US06867221-20050315-C00001
wherein,
    • R1, R2 and R3 each independently represent a hydrogen atom or an alkoxy group;
    • W1 and W2 each independently represent N or CH;
    • X represents O, NR4, CONR4 or NR4CO;
    • R4 represents a hydrogen atom, or an alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl group; and
    • l, m and n each represents a number of 0 or 1,
      a salt thereof and a hydrate thereof are provided.
These compounds have inhibitory effects on both cell adhesion and cell infiltration and are useful as anti-asthmatic agents, anti-allergic agents, anti-rheumatic agents, anti-arteriosclerotic agents, anti-inflammatory agents, anti-Sjogren's syndrome agents or the like.

Description

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel cyclic amine compounds which have inhibitory effects on both cell adhesion and cell infiltration and are useful as anti-asthmatic agents, anti-allergic agents, anti-rheumatic agents, anti-arteriosclerotic agents, anti-inflammatory agents, anti-Sjogren's syndrome agents or the like, and medicines containing such compounds.
2. Description of the Background Art
In various inflammatory diseases, infiltration of leukocytes into inflammatory sites is observed. For example, infiltration of eosinophils into the bronchus in asthma (Ohkawara, Y. et al., Am. J. Respir. Cell Mol. Biol., 12, 4-12 (1995)), infiltration of macrophages and T lymphocytes into the aorta in arteriosclerosis (Sakai, A. et al., Arterioscler Thromb. Vasc. Biol., 17, 310-316 (1997)), infiltration of T lymphocytes and eosinophils into the skin in atopic dermatitis (Wakita, H. et al., J. Cutan. Pathol., 21, 33-39 (1994)) or contact dermatitis (Satoh, T. et al., Eur. J. Immunol., 27, 85-91 (1997)), and infiltration of various leukocytes into rheumatoid synovial tissue (Tak, P P. et al., Clin. Immunol. Immunopathol., 77, 236-242 (1995)), have been reported. Sjogren's syndrome in humans is an organ-specific autoimmune disease characterized by lymphocytic infiltration into the salivary and lacrimal glands, resulting in symptoms of dry mouth and dry eye due to insufficient secretion (Fox R I et al.: “Sjogren's syndrome: proposed criteria for classification” Arthritis Rheum., 29, 577-585(1986)).
Infiltration of these leukocytes is elicited by cytokines, chemokines, lipids, and complements produced in inflammatory sites (Albelda, S M. et al., FASEB J., , 504-512 (1994)). Activated leukocytes adhere to vascular endothelial cells through an interaction called rolling or tethering with endothelial cells activated likewise. Thereafter, the leukocytes transmigrate through endothelium to infiltrate into the inflammatory sites (Springer, T A., Annu. Rev. Physiol., 57, 827-872 (1995)). In adhesion of leukocytes to the vascular endothelial cells in this process, various cell adhesion molecules such as an immunoglobulin superfamily (ICAM-1, VCAM-1 and the like), a selectin family (E-selectin and the like), an integrin family (LFA-1, VLA-4 and the like) and CD44, which are induced on the surfaces of the cells by stimulation by cytokines or the like, play important roles (“Rinsho Meneki (Clinical Immune)”, 30, Supple. 18 (1998)), and a relationship between the disorder state and aberrant expression of the cell adhesion molecules is noted.
Accordingly, an agent capable of inhibiting cell adhesion or cell infiltration can be useful as an agent for preventing and treating allergic diseases such as bronchial asthma, dermatitis, rhinitis and conjunctivitis; autoimmune diseases such as rheumatoid arthritis, nephritis, Sjogren's syndrome, inflammatory bowel diseases, diabetes and arteriosclerosis; and chronic inflammatory diseases. In fact, it has been reported that antibodies against adhesion molecules or leukocytes such as LFA-1, Mac-1 and VLA-4 on antibodies against ICAM-1, VCAM-1, P-selectin, E-selectin and the like on vascular endothelial cells, which become ligands thereof, inhibit infiltration of leukocytes into inflammatory sites in animal models. For example, neutralizing antibodies against VCAM-1 and VLA-4, which is a counter receptor thereof, can delay development of diabetes in an NOD mouse model which spontaneously causes the diabetes (Michie, S A. et al., Curr. Top. Microbiol. Immunol., 231, 65-83 (1998)). It has also been reported that an antibody against VLA-4 or ICAM-1 and its counter receptor, LFA-1, inhibits infiltration of eosinophils in a guinea pig and mouse allergic conjunctivitis model (Ebihara et al., Current Eye Res., 19, 20-25 (1999); Whitcup, S M et al., Clin. Immunol., 93, 107-113 (1999)), and a monoclonal antibody against VCAM-1 inhibits infiltration of leukocytes in a mouse DSS-induced colitis model to attenuate colitis (Soriano, A. et al., Lab. Invest., 80, 1541-1551 (2000)). Further, an anti-VLA-4 antibody and an anti-CD44 antibody reduce the incidence of disease symptoms in a mouse collagen arthritis model (Zeidler, A. et al., Autoimmunity, 21, 245-252 (1995)). Even in cell adhesion molecule deficient-mice, inhibition of infiltration of leukocytes into inflammatory tissues is observed likewise in inflammatory models (Bendjelloul, F. et al., Clin. Exp. Immunol., 119, 57-63 (2000); Wolyniec, W W. et al., Am. J. Respir. Cell Mol. Biol., 18, 777-785 (1998); Bullard, D C. et al., J. Immunol., 157, 3153-3158 (1996)).
However, it is difficult to develop antibody-based drugs because they are polypeptides and so oral administration is a problem. Moreover, the possible side effects due to antigenicity and allergic reactions are problems.
On the other hand, there have been various investigations of low-molecular weight compounds having an inhibitory effect on cell adhesion with a view toward permitting oral administration. These compounds include benzothiophene derivatives (Boschelli, D H. et al., J. Med. Chem., 38, 4597-4614 (1995)), naphthalene derivatives (Japanese Patent Application Laid-Open No. 10-147568), hydroxybenzoic acid derivatives (Japanese Patent Application Laid-Open No. 10-182550), lignans (Japanese Patent Application Laid-Open No. 10-67656), 2-substituted benzothiazole derivatives (Japanese Patent Application Laid-Open No. 2000-086641 through PCT route), condensed pyrazine compounds (Japanese Patent Application Laid-Open No. 2000-319277 through PCT route), 2,6-dialkyl-4-silylphenol (Japanese Patent Application Laid-Open No.2000-509070 through PCT route) and the like. However, the goal has not often been sufficiently achieved under the circumstances. Cyclic diamine compounds described in Japanese Patent Application Laid-Open Nos. 9-143075 and 11-92382 and Japanese Patent Application No.2000-271220 do not exhibit a sufficient inhibitory effect on cell adhesion, and so there is a demand for further improvement in activity.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a substance having inhibitory effects on both cell adhesion and cell infiltration, plus excellent anti-asthmatic effects, anti-allergic effects, anti-rheumatic effects, anti-arteriosclerotic effects, anti-inflammatory effects and anti-Sjogren's syndrome effect.
With the foregoing circumstances in mind, the present inventors carried out an extensive investigation to find a substance which inhibits cell adhesion and cell infiltration. As a result, we found that compounds represented by the general formula (1) having phenyl-pyridyl or biphenyl groups at both ends of the cyclic amine, have excellent cell adhesion-inhibiting effects and cell infiltration-inhibiting effects and are useful as anti-allergic agents, anti-asthmatic agents, anti-rheumatic agents, anti-arteriosclerotic agents or anti-inflammatory agents or anti-Sjogren's syndrome agents.
The present invention provides a cyclic amine compound represented by the following general formula (1):
Figure US06867221-20050315-C00002
wherein,
    • R1, R2 and R3 each independently represent a hydrogen atom, a halogen atom, or hydroxy, alkyl, halogen-substituted alkyl, alkoxy, alkylthio, carboxyl, alkoxycarbonyl or alkanoyl group;
    • W1 and W2 each independently represent N or CH;
    • X represents O, NR4, CONR4 or NR4CO;
    • R4 represents a hydrogen atom, or an alkyl, alkenyl, alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, or substituted or unsubstituted heteroaralkyl group; and
    • l, m and n each represents a number of 0 or 1.
According to the present invention, there is also provided a medicine comprising the above cyclic amine compound, a salt thereof, or a hydrate thereof as an active ingredient.
According to the present invention, there is further provided a pharmaceutical composition comprising the above cyclic amine compound, the salt thereof, or the hydrate thereof and a pharmaceutically acceptable carrier.
According to the present invention, there is still further provided a method for treating a disease caused by cell adhesion and/or cell infiltration, which comprises administering an effective amount of the above cyclic amine compound, a salt thereof, or a hydrate thereof to a patient who requires such treatment.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The compound of the present invention is characterized in that the cyclic amine has two phenyl-pyridyl or biphenyl groups, or phenyl-pyridyl and biphenyl groups. It has not been known at all that compounds having such structure have both of excellent cell adhesion-inhibiting effects and cell infiltration-inhibiting effects.
In the general formula (1), the halogen atoms for R1, R2 and R3 include fluorine, chlorine, bromine and iodine atoms.
The alkyl group for R1, R2, R3 and R4 typically includes straight, branched or cyclic C1-C8 alkyl groups, such as straight or branched C1-C8 alkyl groups, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl groups, and C3-C8 cycloalkyl groups, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl and cyclohexylethyl groups. Among them, particularly preferred are C1-C6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like.
The halogen-substituted alkyl group for R1, R2 and R3 typically includes C1-C8 alkyl groups substituted with 1 to 3 halogen atoms. Among them, particularly preferred are C1-C6 alkyl groups substituted with 1 to 3 halogen atoms, such as trifluoromethyl, 2,2,2-trifluoroethyl, etc.
The alkoxy group typically includes straight, branched or cyclic C1-C8 alkoxy groups, such as straight or branched C1-C8 alkoxy groups, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy and hexyloxy groups; and C3-C8 cycloalkyloxy groups, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxyl, cyclohexylmethyloxy and cyclohexylethyloxy groups. Among them, particularly preferred are C1-C6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy and n-butyloxy groups.
The alkylthio group typically includes C1-C8 alkylthio groups, and is preferably a C1-C6 alkylthio group such as, for example, methylthio, ethylthio, n-propylthio, isopropylthio or the like.
The alkoxycarbonyl group typically includes C1-C6 alkoxycarbonyl groups, and is preferably a C1-C6 alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or the like.
The alkanoyl group typically includes C1-C6 alkanoyl groups and is preferably a C1-C4 alkanoyl group such as acetyl, propionyl, butyryl, isobutyryl or the like.
The alkenyl group for R4 typically includes C3-C8 alkenyl groups and is preferably a C3-C6 alkenyl group such as 2-propenyl, 3-butenyl or the like. The alkynyl group typically includes C3-C8 alkynyl groups and is preferably a C3-C6 alkynyl group such as 2-propynyl, 3-butynyl or the like.
The aryl group for R4 typically includes C6-C14 aryl groups and is preferably phenyl, naphthyl, anthryl, indenyl, indanyl, 5,6,7,8-tetrahydronaphthyl or the like. The heteroaryl group for R4 typically includes heteroaryl groups of 5- or 6-membered ring containing 1 to 4 nitrogen atoms in the ring, and is preferably imidazolyl, pyridyl, pyrimidinyl or the like. The aralkyl group typically includes C6-C14 aryl-C1-C6 alkyl groups such as phenyl C1-C6 alkyl groups and naphthyl C1-C6 alkyl groups, for example, benzyl, naphthylmethyl, phenylethyl, phenylpropyl, etc. The heteroaralkyl group typically includes 5- or 6-membered ring heteroaryl containing 1 to 4 nitrogen atoms-C1-C6 alkyl groups, such as imidazolyl-C1-C6 alkyl, pyridyl-C1-C6 alkyl, pyrimidinyl-C1-C6 alkyl, etc.
The groups which can substitute the above-mentioned aryl, heteroaryl, aralkyl and heteroaralkyl include 1 to 3 groups or atoms selected from alkyl, alkoxy, halogen-substituted alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halogen, nitro, amino, acetylamino, trifluoromethyl and alkylenedioxy, wherein said alkyl, alkoxy and alkylthio include those illustrated for R1˜R3. The alkyl group of the alkylsulfinyl group and alkylsulfonyl group typically includes C1-C3 alkyl groups such as methyl, ethyl, n-propyl and isopropyl groups. The halogen-substituted alkoxy includes C1-C8 alkoxy groups substituted by 1 to 3 halogen atoms, and is preferably a C1-C6 alkoxy group substituted by 1 to 3 halogen atoms such as trifluoromethoxy or 2,2,2-trifluoroethoxy. The alkylenedioxy group typically includes C1-C3 alkylenedioxy groups such as methylenedioxy, ethylenedioxy and propylenedioxy groups.
Preferably, X represents NR4. More preferably, X represents NR4 and R4 represents a substituted or unsubstituted C6-C14 aryl group or a substituted or unsubstituted 5- or 6-membered ring heteroaryl group containing 1 to 4 nitrogen atoms in the ring. The compounds of the formula (1) wherein X represents NR4 have particularly strong cell adhesion-inhibiting action as shown later in Test Example 1.
Preferably, R1, R2 and R3 are attached to the phenyl group at the 3, 4 and 5-positions thereof. In this case, it is more preferable that R1 and R3 (at the 3- and 5-positions of the phenyl ring) are an alkoxy group or a halogen. It is also preferable that R2 (at the 4-position of the phenyl ring) is a hydrogen atom, a halogen atom, or a hydroxy, alkyl, halogen-substituted alkyl, alkoxy, alkylthio, carboxy, alkoxycarbonyl or alkanoyl group. l denotes 0 or 1, and is preferably 1.
Preferably, W1 represents N.
Preferably, W2 represents N.
Most preferable compounds include the compounds of the formula (1), wherein X represents NR4, and R4 represents a substituted or unsubstituted C6-C14 aryl group or a substituted or unsubstituted 5- or 6-membered ring heteroaryl group containing 1 to 4 nitrogen atoms in the ring. Particularly preferably, R4 represents a phenyl or pyridyl group which may be substituted with one or two groups or atoms selected from halogen, alkyl, alkoxy, alkylthio, trifluoromethyl and alkylenedioxy.
No particular limitation is imposed on the salts of the compounds (1) according to the invention as long as they are pharmaceutically acceptable salts. Examples include the acid-addition salts of mineral acids, such as hydrochlorides, hydrobromides, hydroiodides, sulfates and phosphates; and acid-addition salts of organic acids, such as benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, oxalates, maleates, fumarates, tartrates, citrates and acetates.
The compounds of formula (1) may be present in the form of solvates typified by hydrates, and the solvates are embraced in the present invention.
The compounds of formula (1) can be prepared in accordance with the following processes A˜L:
  • Process A: Preparation of the compound of the formula (1) wherein l=1, m=0, n=1 and X=CONR4
    Figure US06867221-20050315-C00003
  •  wherein, W1, W2, R1, R2, R3 and R4 are as defined above, W3 has the same meaning as W1 or W2, and B denotes a leaving group such as a halogen atom, or methanesulfonyloxy or p-toluenesulfonyloxy group.
Compound (2) and an N-(2-nitro)benzenesulfonylamine derivative (3) are reacted to give compound (4). The resulting compound (4) is treated with thiophenol in the presence of a base such as potassium carbonate to eliminate the 2-nitrobenzenesulfonyl group, thereby giving amine compound (5). Alternatively, when R4 is H, it is possible to react compound (2) with potassium phthalimide and then treat the resulting phthalimide derivative (6) with hydrazine to give the corresponding amine compound (5).
On the other hand, compound (2) is reacted with ethyl isonipecotate (7) in a solvent such as acetonitrile, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dioxane, toluene, benzene, etc. in the presence of a base such as potassium carbonate or the like at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature overnight, to give compound (8). The compound (8) is subjected to a usual alkaline hydrolysis to give the corresponding carboxylic acid compound (9).
The carboxylic acid compound (9) is reacted with the amine compound (5) using a dehydration condensing agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (water-soluble carbodiimide), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) or the like in a solvent such as chloroform, dichloroethane, THF, dioxane, acetonitrile, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 12 hours, to give an end product (1A).
  • Process B: Preparation of the compound of the formula (1) wherein l=1, m=0, n=1 and X=O
    Figure US06867221-20050315-C00004
  •  wherein, B, W1, W2, R1, R2 and R3 are as defined above, and J denotes a protecting group such as benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzoyl or benzyl group. Incidentally, in the reaction schemes shown above and below, the expression “(W2→W1)” following the term “compound(2)” means that W2 in the formula representing compound (2) is changed to W1.
4-hydroxypiperidine compound (10) with a protected amino group is reacted with compound (2) in the presence of sodium hydride or potassium iodide in a solvent such as DMF, DMSO, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 2 days, to give compound (11). The protecting group in the compound (11) is removed in a known manner. The resulting compound (12) is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give an end product (1B).
  • Process C: Preparation of the compound of the formula (1) wherein l=1, m=0, n=0, X=NR4CO and R4=H or Me
    Figure US06867221-20050315-C00005
  •  wherein, B, W1, W2,, R1, R2 and R3 are as defined above, and R4denotes a hydrogen atom or methyl group.
Isonipecotamide (13) is reacted with compound (2) in the presence of a base such as potassium carbonate, sodium carbonate or the like in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give compound (14). The compound (14) is subjected to Hofmann rearrangement reaction to give amine compound (15).
On the other hand, by subjecting the compound (14) to Hofmann rearrangement reaction in ethanol, carbamate compound (16) is obtained. Then, by subjecting the compound (16) to a reduction reaction using lithium aluminum hydride, methylamine compound (17) is obtained.
By reacting carboxylic acid compound (18) with the amine compound (15) or methylamine compound (17) similarly to the condensation reaction in Process A, an end compound (1C) is obtained.
  • Process D: Preparation of the compound of the formula (1) wherein l=1, m=0, n=1 and X=NR4
    Figure US06867221-20050315-C00006
    Figure US06867221-20050315-C00007
  •  wherein, B, W1, W2, R1, R2 and R3 are as defined above, and R4 denotes an alkyl, alkenyl, alkynyl, aralkyl or heteroaralkyl group.
The amine compound (15) mentioned in the above is reacted with 2-nitrobenzenesulfonyl chloride (19) according to a known manner to give compound (20). The compound (20) is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane or the like at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give compound (21). The benzenesulfonyl group of the compound (21) is removed similarly to the procedure for the compound (4) in Process A to give an end compound (1D) (R4=H). The compound (1D) is reacted with R4—B in the presence of a base such as sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate or the like in a solvent such as acetonitrile, THF, dioxane, chloroform, dichloromethane, DMF, DMSO or the like at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at 80° C. for 12 hours, to give compound (1D′).
On the other hand, the methylamine compound (17) is reacted compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane or the like at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give an end compound (1D″) (R4=Me).
  • Process E: Preparation of the compound of the formula (1) wherein l=1, m=0 or 1, n=1 and X=NR4,
    Figure US06867221-20050315-C00008
  •  wherein, B, J, W1, W2, R1, R2 and R3 are as defined above, and R4 denotes an alkyl, alkenyl, alkynyl, aralkyl or heteroaralkyl group.
Aminopiperidine derivative (22) in which the amino group on the ring is protected is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane or the like at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give compound (23). The compound (23) is reacted with R4—B in the presence of a base such as sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate or the like in a solvent such as acetonitrile, THF, dioxane, chloroform, dichloroethane, DMF, DMSO or the like at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at 80° C. for 12 hours, to give compound (24). After removal of the protecting group, the compound (25) is reacted compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane or the like at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give compound (1E).
  • Process F: Preparation of the compound of the formula (1) wherein l=1, m=0, n=1 and X=NR4,
    Figure US06867221-20050315-C00009
  •  wherein, B, W1, W2, R1, R2 and R3 are as defined above, and R4 denotes an alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl or heteroaryl group.
4-piperidone ethylene ketal (26) is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give compound (27), which in turn is deketalized by using an acid to give ketone compound (28).
On the other hand, 4-piperidone (29) is reacted compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane or the like at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give compound (28). Using the compound (28), amine compound (30) can be prepared according to either of the following two synthesis processes:
  • Synthesis process 1: The compound (28) is reacted with an amine compound of the formula: R4—NH2 in the presence of molecular sieves in toluene or benzene at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at reflux temperature for 12 hours, followed by reaction with a reducing agent such as sodium borohydride or sodium cyanoborohydride at a temperature between 0° C. and a reflux temperature for several minutes to several days, preferably at room temperature for 1 hour, to give the amine compound (30).
  • Synthesis process 2: The compound (28) is reacted with an amine compound of the formula: R4—NH2 in the presence of a reducing agent such as sodium triacetoxy boron hydride in a solvent such as dichloromethane, 1,2-dichloroethane, methanol, ethanol, etc. at a temperature between 0° C. and a reflux temperature for several minutes to several days, preferably at room temperature for 4 hours, to give the amine compound (30).
The resulting compound (30) is reacted compound (2) in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give an end product (1F).
  • Process G: Preparation of the compound of the formula (1) wherein l=1, m=0, n=1 and X=NR4
    Figure US06867221-20050315-C00010
  •  wherein, B, J, W1, W2, R1, R2 and R3 are as defined above, and R4 denotes an alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl or heteroaryl group.
4-piperidone derivative (31) in which the amino group on the ring is protected is reacted with an amine compound R4—NH2 similarly to the procedure for preparation of compound (30) in Process F to give compound (32). The compound (32) is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give compound (33). After removal of the protecting group from the compound (33), the resulting compound (34) is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give an end product (1G).
  • Process H: Preparation of the compound of the formula (1) wherein l=0, m=0, n=1 and X=NH
    Figure US06867221-20050315-C00011
    Figure US06867221-20050315-C00012
  •  wherein, B, J, W1, W2, R1, R2 and R3 are as defined above.
3-aminopyrrolidine derivative (35) with a protected amino group on the ring is reacted with 2-nitrobenzenesulfonyl chloride (19) under usual conditions to give a benzenesulfonyl derivative (36). The derivative (36) is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give compound (37). The protecting group of the amino group is removed from the compound (37) to give compound (38), which in turn is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give compound (39). By subjecting the compound (39) to a reaction similar to that in the preparation of compound (5) in Process A, an end product (1H) is obtained.
  • Process I: Preparation of the compound of the formula (1) wherein l=0, m=0, n=1 and X=NR4
    Figure US06867221-20050315-C00013
    Figure US06867221-20050315-C00014
  •  wherein, B, J, W1, W2, R1, R2 and R3 are as defined above, and R4 denotes an alkyl, alkenyl, alkynyl or aralkyl group.
Compound (36) is reacted with R4—B in the presence of a base such as sodium carbonate, potassium carbonate, etc. in a solvent such as acetonitrile, THF, dioxane, chloroform, dichloroethane, DMF, DMSO, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at 80° C. for 12 hours, to give compound (40). The amino-protecting group is removed from the compound (40), and the resulting compound (41) is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give compound (42). By subjecting the compound (42) to a reaction similar to that in the preparation of compound (5) in Process A, compound (43) is obtained. The compound (43) is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give an end product (1I).
  • Process J: Preparation of the compound of the formula (1) wherein R2=OH
    Figure US06867221-20050315-C00015
  •  wherein, X, W1, W2, R1, R3, l, m and n have the same meanings as initially defined.
By reacting methoxy compound (1J) with iodotrimethylsilane in a solvent such as toluene, chloroform, dichloromethane, etc. at a temperature between −25° C. and a reflux temperature for several minutes to several days, preferably at 0° C. for 2 hours, there can be obtained an end product (1J′).
  • Process K: Preparation of the compound of the formula (1) wherein l=1, m=0, n=0 and X=NR4CO
    Figure US06867221-20050315-C00016
  •  wherein, B, J, W1, W2, R1, R2 and R3 are as defined above, and R4 denotes an alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, aryl or heteroaryl group.
Compound (32), which is described in the Process G, is reacted with compound (18) in the similar procedure as described in the preparation of compound (1A) in Process A to give compound (44). After removal of the protecting group from the compound (44), the resulting compound (45) is reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at room temperature for 4 hours, to give an end product (1K).
  • Process L: Preparation of the compound of the formula (1) wherein l=1, m=O, n=1 and X=alkylsulfonylphenylamino group
    Figure US06867221-20050315-C00017
  •  wherein, B, W1, W2, R1, R2 and R3 are as defined above.
Compound (34), which was prepared in the Process G (wherein X denotes alkylthiophenylamino group), is reacted with an oxdation agent such as 3-chloroperbenzoic acid, peracetic acid, hydrogen peroxide, etc. in the known manner to give an alkylsulfonyl derivative (46). Compound (46) is then reacted with compound (2) in the presence of a base such as potassium carbonate in a solvent such as acetonitrile, DMF, DMSO, THF, dioxane, etc. at a temperature between 0° C. and a reflux temperature for several hours to several days, preferably at 70° C. overnight, to give an end product (1L).
The compounds (1) according to the present invention are obtained by any of the above-described processes and may further be purified by using an ordinary purification means such as recrystallization or column chromatography as needed. As needed, the compounds may also be converted into the desired salts or solvates in a method known per se in the art. When the compounds (1) have an asymmetric carbon atom, the present invention includes any configurational isomers.
The compounds (1) according to the present invention, or salts or solvates thereof thus obtained have an excellent inhibitory effect on cell adhesion as demonstrated in the examples, which will be described subsequently, and are useful as medicines for treatment and prevention of diseases of animals including humans, caused by cell adhesion or cell infiltration, for example, asthma, allergy, rheumatism, arteriosclerosis, inflammation, Sjogren's syndrome, etc.
The medicine according to the present invention comprises a compound (1), a salt thereof, or a solvate thereof as an active ingredient. The form of administration may be suitably selected as necessary for the therapeutic application intended without any particular limitation, including oral preparations, injections, suppositories, ointments, inhalants, eye drops, nose drops and plasters. A composition suitable for use in these administration forms can be prepared by blending a pharmaceutically acceptable carrier in accordance with the conventional preparation method publicly known by those skilled in the art.
When an oral solid preparation is formulated, an excipient, and optionally, a binder, disintegrator, lubricant, colorant, a taste corrigent, a smell corrigent and the like are added to compound (1) and the resulting composition can be formulated into tablets, coated tablets, granules, powders, capsules, etc. in accordance with methods known in the art.
As such additives described above, any additives may be used which are generally used in the pharmaceutical field. Examples include excipients such as lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose and silicic acid; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate and polyvinyl pyrrolidone; disintegrators such as dry starch, sodium alginate, agar powder, sodium hydrogencarbonate, calcium carbonate, sodium lauryl sulfate, monoglyceryl stearate and lactose; lubricants such as purified talc, stearic acid salts, borax and polyethylene glycol; and taste corrigents such as sucrose, orange peel, citric acid and tartaric acid.
When an oral liquid preparation is formulated, a taste corrigent, buffer, stabilizer, smell corrigent and/or the like are added to compound (1) and the resulting composition can be formulated into internal liquid preparations, syrup preparations, elixirs, etc. in accordance with methods known in the art. In this case, vanillin as the taste corrigent, may be used. As the buffer, sodium citrate may be mentioned. As examples of the stabilizer, tragacanth, gum arabic and gelatin may be mentioned.
When an injection is formulated, a pH adjustor, buffer, stabilizer, isotonicity agent, local anesthetic and the like may be added to compound (1) according to the present invention, and the resultant composition can be formulated into subcutaneous, intramuscular and intravenous injections in accordance with methods known in the art. Examples of the pH adjustor and buffer in this case include sodium citrate, sodium acetate and sodium phosphate. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid and thiolactic acid. Examples of the local anesthetic include procaine hydrochloride and lidocaine hydrochloride. Examples of the isotonicity agent include sodium chloride and glucose.
When a suppository is formulated, a carrier preparation known in the art, for example, polyethylene glycol, lanoline, cacao butter, fatty acid triglyceride or the like, and optionally, a surfactant such as Tween (trade mark) and the like are added to the compound (1), and the resultant composition can be formulated into suppositories in accordance with methods known in the art.
When an ointment is formulated, a base material, stabilizer, wetting agent, preservative and the like, which are generally used, are blended with compound (1) as needed, and the resulting blend is mixed and formulated into ointments in accordance with known method known methods. Examples of the base material include liquid paraffin, white vaseline, bleached beeswax, octyldodecyl alcohol and paraffin. Examples of the preservative include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate and propyl p-hydroxybenzoate.
Besides the above preparations, inhalants, eye drops and nose drops may also be formulated in accordance with known methods.
The dose of the medicine according to the present invention varies according to the age, weight and condition of the patient to be treated, the administration method, the number of times of administration, and the like. It is however preferred that the medicine is generally orally or parenterally administered at once or in several portions in a dose of 1 to 1,000 mg per day in terms of compound (1), for an adult.
The present invention will hereinafter be described in more detail by Examples. However, the present invention is not limited to these examples.
PREPARATION EXAMPLE 1 Synthesis of ethyl 2-(3,4,5-trimethoxyphenyl)isonicotinate
Figure US06867221-20050315-C00018
3,4,5-Trimethoxyphenylboronic acid (20.10 g) and ethyl 2-chloroisonicotinate (18.56 g) were suspended in a mixted solvent of toluene (200 mL) and THF(100 mL), and to the suspension 2 M sodium carbonate (200 mL) and tetrakis(triphenyl phosphine) palladium(0) (5.78 g) were added. The mixture was stirred at 90° C. overnight under an argon atmosphere. Ethyl acetate was added to the reaction mixture to separate an organic layer. The organic layer was washed with brine, dried over anhydrous sodium magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using hexane-ethyl acetate (5:1) to give the title compound.
Yield: 27.99 g (88%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (t, 3H, J=7.0 Hz), 3.92 (s, 3H), 3.99 (s, 6H), 4.46 (q, 2H, J=7.0 Hz), 7.30 (s, 2H), 7.76 (dd, 1H, J=5.1 Hz, 1.6 Hz), 8.24 (dd, 1H, J=1.6 Hz, 0.8 Hz), 8.81 (dd, 1H, J=5.1 Hz, 0.8 Hz).
PREPARATION EXAMPLE 2 Synthesis of 4-hydroxymethyl-2-(3,4,5-trimethoxyphenyl)pyridine
Figure US06867221-20050315-C00019
Ethyl 2-(3,4,5-trimethoxyphenyl)isonicotinate (24.57 g) was dissolved in dry THF (200 mL), and to the solution lithium aluminum hydride (2.94 g) was added at 0° C. under an argon atmosphere. The mixture was stirred at 0° C. for 1 hour as it is. A small amount of water and then sodium sulfate were added to the reaction mixture, and the reaction mixture was filtered through celite. The filtrate was evaporated, and the reultant crude crystals were recrystalized from ethyl acetate-hexane to give the title compound.
Yield: 17.53 g (82%). 1H-NMR (400 MHz, CDCl3) δ: 3.90 (s, 3H), 3.95 (s, 6H), 4.79 (s, 2H), 7.19 (d, 1H, J=5.1 Hz), 7.21 (s, 2H), 7.66 (s, 1H), 8.60 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 3 Synthesis of 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine
Figure US06867221-20050315-C00020
4-hydroxymethyl-2-(3,4,5-trimethoxyphenyl)pyridine(19.18 g) was dissolved in chloroform (100 mL), and to the solution thinly chloride (10.2 mL) was added at 0° C. After 30 minutes, the mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was washed with aqaueous saturated sodium hydrogendcarbonate and brine, dried over anhydrous sodium sulfate and evaporated. The residue was then recrystallized from ethyl acetate-hexane to give the title compound as pale yellow crystalline powder.
Yield: 18.24 g (89%). 1H-NMR (400 MHz, CDCl3) δ: 3.91 (s, 3H), 3.97 (s, 6H), 4.61 (s, 2H), 7.24 (s, 2H), 7.26 (d, 1H, J=5.1 Hz), 7.68 (s, 1H), 8.67 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 4 Synthesis of N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]phthalimide
Figure US06867221-20050315-C00021
To a solution of 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (881 mg) in chloroform (10 mL) was added potassium phthalimide (556 mg). The mixture was stirred at room temperature overnight and water was added. After separating the organic layer, the aqueous layer was extracted with chloroform. Organic layers were combined, dried over anhydrous magnesium sulfate and evaporated to give the title compound as white powder.
Yield: 1.16 g (96%).
PREPARATION EXAMPLE 5 Synthesis of 4-aminomethyl-2-(3,4,5-trimethoxyphenyl)pyridine
Figure US06867221-20050315-C00022
To a suspension of N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]phthalimide (1.16 g) in ethanol (30 mL) was added hydrazine monohydrate (1 mL). The mixture was refluxed for 3 hours. After cooling, the precipitates were filtered off. The filtrate was evaporated and the residue was dissolved in chloroform. The solution was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and evaporated to give the title compound as pale yellow oil.
Yield: 418 mg (53%).
PREPARATION EXAMPLE 6 Synthesis of ethyl 1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine-4-carboxylate
Figure US06867221-20050315-C00023
To a solution of ethyl piperidine-4-carboxylate (514 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (969 mg) in acetonitrile (20 mL) was added potassium carbonate (452 mg). The mixture was stirred at room temperature for 4 hours and evaporated. The residual oil was subjected to a column of silica gel and eluted using hexane-ethyl acetate (2:1) and then chloroform-methanol (40:1). Fractions containing the product were collected and evaporated to give the title compound as white prisms.
Yield: 1.20 g (88%). 1H-NMR (400 MHz, CDCl3) δ: 1.25 (t, 3H, J=7.0 Hz), 1.72-1.93 (m, 4H), 2.10 (t, 2H, J=9.8 Hz), 2.27-2.35 (m, 1H), 2.86 (d, 2H, J=11.3 Hz), 3.55 (s, 2H), 3.91 (s, 3H), 3.98 (s, 6H), 4.14 (q, 2H, J=7.0 Hz), 7.21 (d, 1H, J=4.9 Hz), 7.24 (s, 2H), 7.63 (s, 1H), 8.59 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 7 Synthesis of 1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine-4-carboxylic acid
Figure US06867221-20050315-C00024
To a solution of ethyl 1-[[2-(3,4,5-trimethoxyphenyl)prydine-4-yl]methyl]piperidine-4-carboxylate (760 mg) in ethanol (10 mL) was added 1 M sodium hydroxide (10 mL). The mixture was stirred at room temperature for 4 hours and evaporated. The residue was dissolved in water (20 mL) and 5% aqueous potassium hydrogen sulfate was added dropwise until pH of the solution became 7. Precipitates were collected and the product was used for the next steps without further purification.
Yield: 779 mg (theoretical amount).
EXAMPLE 1 Synthesis of 1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methylaminocarbonyl]piperidine maleate
Figure US06867221-20050315-C00025
To a solution of 1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine-4-caroxylic acid (97 mg) and 4-aminomethyl-2-(3,4,5-trimethoxyphenyl) pyridine (68 mg) in acetonitrile (5 mL) was added HBTU (95 mg). The mixture was stirred at room temperature for 12 hours and evaporated. The residual oil was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and evaporated. Resulting residue was applied to a column of silica gel and eluted using chloroform-methanol (40:1) and then chloroform-methanol (20:1). Fractions containing the product were collected and evaporated. The free base of the product was then converted to a maleate by the usual method.
Yield: 93 mg (49%). 1H-NMR (400 MHz, measured as a maleate, DMSO-d6) δ: 1.87-2.01 (m, 4H), 2.48-2.56 (m, 1H), 2.78-2.86 (m, 2H), 3.26-3.31 (m, 2H), 3.78 (s, 3H), 3.79 (s, 3H), 3.87 (s, 6H), 3.90 (s, 6H), 4.15 (s, 2H), 4.39 (d, 2H, J=5.9 Hz), 6.16 (s, 2H), 7.16 (d, 1H, J=5.9 Hz), 7.35 (s, 2H), 7.39 (d, 1H, J=5.9 Hz), 7.39 (s, 2H), 7.73 (s, 1H), 7.95 (s, 1H), 8.15 (d, 1H, J=5.9 Hz), 8.54 (d, 1H, J=4.9 Hz), 8.68 (d, 1H, J=4.9 Hz).
PREPARATION EXAMPLE 8 Synthesis of 1-(benzyloxycarbonyl)-4-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyloxy]piperidine
Figure US06867221-20050315-C00026
To a solution of 1-(benzyloxycarbonyl)-4-hydroxypiperidine (1.00 g) in DMF (20 mL) was added sodium hydride (55%, dispersion in mineral oil, 222 mg). The mixture was stirred at room temperature for 1 hour and then, 4-chlolromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (1.37 g) and potassium iodide (755 mg) was added. The mixture was stirred at 70° C. overnight, poured into water and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residual oil was applied to a column of silica gel and column chromatography was performed using chloroform-methanol (99:1) as an eluent giving the title compound.
Yield: 213 mg (10%). 1H NMR (400 MHz, CDCl3) δ: 1.63 (br, 2H), 1.89 (br, 2H), 3.20-3.35 (m, 2H), 3.57-3.68 (m, 1H), 3.84-3.92 (m, 5H), 3.94 (s, 6H), 4.62 (s, 2H), 5.11 (s, 2H), 7.21-7.35 (m, 8H), 7.61 (s, 1H), 8.61 (d, 1H, J=5.0 Hz).
PREPARATION EXAMPLE 9 Synthesis of 4-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyloxy]piperidine
Figure US06867221-20050315-C00027
To a solution of 1-(benzyloxycarbonyl)-4-[[2-(3,4,5-trimethoxyphenyl) pyridin-4-yl]methyloxy]piperidine (213 mg) in methanol (10 mL) was added 40% aqueous potassium hydroxide (10 mL). The mixture was stirred at 100° C. for 3 hours and evaporated. Water was added to the residue and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residual oil was subjected to column chromatography of silica gel using chloroform-ammonia saturated methanol (20:1) to give the title compound.
Yield: 93 mg (60%). 1H NMR (400 MHz, CDCl3) δ: 1.55-1.68 (m, 2H), 2.01 (br, 2H), 2.67-2.72 (m, 2H), 3.13-3.18 (m, 2H), 3.50-3.60 (m, 1H), 3.91 (s, 3H), 3.97 (s, 6H), 4.64 (s, 2H, 7.22 (d, 1H, J=4.3 Hz), 7.24 (s, 2H), 7.64 (s, 1H), 8.63 (d, 1H, J=5.1 Hz).
EXAMPLE 2 Synthesis of 1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyloxy]piperidine trihydrochloride
Figure US06867221-20050315-C00028
4-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyloxy]piperidine (70 mg), 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (22 mg), potassium carbonate (56 mg) and potassium iodide (40 mg) were suspended in acetonitrile (5 mL). The mixture was stirred at room temperature for 5 hr and evaporated. Chloroform and water were added to the residual oil and the organic layer was separated. Aqueous layer was then extracted with chloroform and the organic layers were combined, dried over anhydrous magnesium sulfate and evaporated. The residue was applied to a column of silica gel using chloroform-methanol (40:1) as an eluent. Fractions containing the product were collected and evaporated. The title compound was obtained by converting the free base to a trihydrochloride.
Yield: 42 mg (39%). 1H NMR (400 MHz, measured as a free base, CDCl3) δ: 1.53-2.42 (m, 6H), 2.80 (br, 2H), 3.57 (br, 3H), 3.88 (s, 6H), 3.94 (s, 6H), 3.95 (s, 6H), 4.60 (s, 2H), 7.18-7.24(m, 6H), 7.61 (s, 2H), 8.58-8.61 (m, 2H).
PREPARATION EXAMPLE 10 Synthesis of (3S)-1-(tert-butoxycarbonyl)-3-[(2-nitrobenzene)sulfonylamino]pyrrolidine
Figure US06867221-20050315-C00029
To an ice-cooled solution of (3S)-3-amino-1-(tert-butoxycarbonyl) pyrrolidine (404 mg) and triethylamine (220 mg) in THF (5 mL) was added 2-nitrobenzenesulfonyl chloride (481 mg). The mixture was stirred at room temperature for 30 minutes and evaporated. Ethyl acetate was added to the residue. The solution was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residual oil was subjected to a column of silica gel and column chromatography was performed using chroloform-methanol (20:1) as an eluent. Fractions containing the product were collected and evaporated to give the title compound as pale yellow amorphous.
Yield: 597 mg (74%). 1H-NMR (400 MHz, CDCl3) δ: 1.44 (s, 9H), 1.80-2.12 (m, 2H), 3.14-3.44 (m, 4H), 4.02 (br, 1H), 5.48 (d, 1H, J=7.2 Hz), 7.77 (t, 2H, J=4.4 Hz), 7.87-7.90 (m, 1H), 8.17-8.19 (m, 1H).
PREPARATION EXAMPLE 11 Synthesis of (3S)-1-(tert-butoxycarbonyl)-3-[N-methyl-N-(2-nitrobenzene) sulfonylamino]pyrrolidine
Figure US06867221-20050315-C00030
To a suspension of (3S)-1-(tert-butoxycarbonyl)-3-[(2-nitrobenzene) sulfonylamino]pyrrolidine (371 mg) and potassium carbonate (141 mg) in acetonitrile (10 mL) was added methyl iodide (141 mg). The mixture was stirred at 60° C. for 2 hours and evaporated. Ethyl acetate was added to the mixture. The solution was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate and evaporated. The residue was applied to a column of silica gel using hexane-ethyl acetate (2:1) as an eluent. Fractions containing the product were collected and evaporated to give the title compound as yellow syrup.
Yield: 365 mg (95%). 1H-NMR (400 MHz, CDCl3) δ: 1.44 (s, 9H), 1.95 (br, 1H), 2.09 (br, 1H), 2.87 (s, 3H), 3.20-3.31 (m, 2H), 3.53 (br, 2H), 4.58 (br, 1H), 7.65 (br, 1H), 7.71 (br, 2H), 8.04 (br, 1H).
PREPARATION EXAMPLE 12 Synthesis of (3S)-3-[N-methyl-N-(2-nitrobenzene)sulfonylamino]pyrrolidine
Figure US06867221-20050315-C00031
To an ice-cooled solution of (3S)-1-(tert-butoxycarbonyl)-3-[N-methyl-N-(2-nitrobenzenesulfonyl)amino]pyrrolidine (365 mg) in dichloromethane (25 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 3 hours and evaporated. The residue was dissolved in chloroform. The solution was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate and evaporated to give the title compound as yellow syrup.
Yield: 135 mg (50%). 1H-NMR (400 MHz, CDCl3) δ: 1.69-1.74 (m, 1H), 1.87 (br, 1H), 1.95-2.02 (m, 1H), 2.80 (dd, 1H, J=11.7 Hz, 5.7 Hz), 2.84-2.91 (m, 4H), 2.96-3.05 (m, 1H), 3.10 (dd, 1H, J=11.7 Hz, 8.2 Hz), 4.48-4.56 (m, 1H), 7.61-7.63 (m, 1H), 7.66-7.73 (m, 2H), 8.01-8.04 (m, 1H).
PREPARATION EXAMPLE 13 Synthesis of (3S)-3-[N-methyl-N-(2-nitrobenzene)sulfonylamino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]pyrrolidine
Figure US06867221-20050315-C00032
(3S)-3-[N-methyl-N-(2-nitrobenzene)sulfonylamino]pyrrolidine (135 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (139 mg) were coupled in the same manner as described in Example 2 to give the title compound as yellow amorphous.
Yield: 247 mg (96%). 1H-NMR (400 MHz, CDCl3) δ: 1.80-1.87 (m, 1H), 2.15-2.30 (m, 2H), 2.52 (dd, 1H, J=10.5 Hz, 8.2 Hz), 2.71 (dd, 1H, J=10.5 Hz, 8.2 Hz), 2.90 (dt, 1H, J=8.8 Hz, 2.9 Hz), 2.96 (s, 3H), 3.53 (d, 1H, J=13.9 Hz), 3.68 (d, 1H, J=13.9 Hz), 3.90 (s, 3H), 3.96 (s, 6H), 4.61-4.68 (m, 1H), 7.16 (dd, 1H, J=4.9 Hz, 1.2 Hz), 7.21 (s, 2H), 7.58-7.60 (m, 2H), 7.64-7.69 (m, 2H), 7.99-8.02 (m, 1H), 8.58 (d, 1H, J=4.9 Hz,).
PREPARATION EXAMPLE 14 Synthesis of (3S)-3-methylamino-1-[[2-(3,4,5-trimethoxyphenyl)-pyridin-4-yl]methyl]pyrrolidine
Figure US06867221-20050315-C00033
To a solution of (3S)-3-[N-methyl-N-(2-nitrobenzene)sulfonylamino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]pyrrolidine (242 mg) in acetonitrile (5 mL) was added potassium carbonate (94 mg) and thiophenol (75 mg). The mixture was stirred at 80° C. for 3 hours and evaporated. Ethyl acetate was added to the mixture, the solution was washed with saturated aqueous sodium hydrogen carbonate, water, and bine, dried over anhydrous sodium sulfate and evaporated. The residual oil was subjected to preparative TLC using chloroform-methanol (20:1) as a solvent system giving yellow syrup of the title compound.
Yield: 104 mg (64%). 1H-NMR (400 MHz, CDCl3) δ: 1.32 (br, 1H), 1.56-1.64 (m, 1H), 2.11-2.17 (m, 1H), 2.38 (s, 3H), 2.44 (dd, 1H, J=7.4 Hz, 4.5 Hz), 2.50-2.55 (m, 1H), 2.66-2.75 (m, 2H), 3.20-3.26 (m, 1H), 3.66 (s, 2H), 3.90 (s, 3H), 3.97 (s, 6H), 7.21 (d, 1H, J=4.1 Hz), 7.25 (s, 2H), 7.64 (s, 1H), 8.59 (d, 1H, J=4.9 Hz).
EXAMPLE 3 Synthesis of (3S)-3-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]pirrolidine tertrahydrochloride
Figure US06867221-20050315-C00034
(3S)-3-methylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]pyrrolidine (104 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (85 mg) was condensed in the same manner as described in Example 2. Yellow syrup obtained was converted to a tetrahydrochloride by the usual method giving the title compound as yellow powder.
Yield: 151 mg (68%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.89-1.92 (m, 1H), 2.04-2.08 (m, 1H), 2.18 (s, 3H), 2.60-2.76 (m, 4H), 3.25-3.29 (m, 1H), 3.53 (d, 1H, J=14.3 Hz), 3.62 (d, 1H, J=14.3 Hz), 3.64 (d, 1H, J=13.9 Hz), 3.73 (d, 1H, J=13.9 Hz), 3.89 (s, 6H), 3.95 (s, 6H), 3.96 (s, 6H), 7.20-7.21 (m, 2H), 7.23 (s, 2H), 7.24 (s, 2H), 7.61 (s, 1H), 7.65 (s, 1H), 8.59 (d, 1H, J=5.7 Hz), 8.60 (d, 1H, J=5.3 Hz).
PREPARATION EXAMPLE 15 Synthesis of 1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine-4-carboxamide
Figure US06867221-20050315-C00035
Piperidine-4-carboxamide (385 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (881 mg) were condensed by the same method as described in Example 2 to give the title compound as white needles.
Yield: 1.01 g (87%). 1H-NMR (400 MHz, CDCl3) δ: 1.70-1.88 (m, 4H), 2.01-2.23 (m, 3H), 2.95 (d, 2H, J=11.0 Hz), 3.56 (s, 2H), 3.90 (s, 3H), 3.98 (s, 6H), 5.46 (d, 2H, J=16.3 Hz), 7.21 (d, 1H, J=5.0 Hz), 7.24 (s, 2H), 7.64 (s, 1H), 8.59 (d, 1H, J=5.0 Hz).
PREPARATION EXAMPLE 16 Synthesis of 4-amino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00036
To a solution of 1-[[2-(3,4,5-trimethoxypheyl)pyridin-4-yl]methyl]piperidine-4-carboxamide (192 mg) in a mixed solvent of water (50 mL) and acetonitrile (50 mL) was added [bis(trifluoroacetoxy)iodo]benzene (323 mg). The mixture was stirred at room temperature overnight and evaporated. Saturated aqueous sodium hydrogen carbonate was added to the residue and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. Yellow syrup obtained was then converted to trihydrochloride which gave yellow powder. The title compound was used for next step without further purification.
Yield: 201 mg (theoretical amount).
PREPARATION EXAMPLE 17 Synthesis of 2-(3,4,5-trimethoxyphenyl)isonicotinic acid
Figure US06867221-20050315-C00037
To a solution of ethyl 2-(3,4,5-trimethoxyphenyl)isonicotinate (3.17 g) in ethanol (40 mL) was added 10% potassium hydroxide (2.42 g). The mixture was stirred at room temperature for 5 hours and evaporated. Water was added to the residue and pH was adjusted to 7. White precipitates of the title compound were collected by filtration and the compound was used for next step without further purification.
Yield: 2.60 g (90%).
EXAMPLE 4 Synthiesis of 4-[2-(3,4,5-trimethoxyphenyl)pyridin-4-carbonylamino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine maleate
Figure US06867221-20050315-C00038
2-(3,4,5-trimethoxyphenyl)isonicotinic acid (72 mg) and 4-amino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (117 mg) were condensed in the same manner as described in Example 1. The title compound was obtained as a maleate.
Yield: 173 mg (93%). 1H-NMR (400 MHz, measured as a maleate, DMSO-d6) δ: 1.82-1.94 (m, 2H), 2.03-2.08 (m, 2H), 2.77-2.83 (m, 2H), 3.20-3.27 (m, 2H), 3.79 (s, 6H), 3.90 (s, 12H), 4.00 (br, 1H), 4.06 (s, 2H), 6.15 (s, 2H), 7.36-7.38 (m, 1H), 7.39 (s, 2H), 7.41 (s, 2H), 7.61-7.63 (m, 1H), 7.90 (s, 1H), 8.12 (s, 1H), 8.27-8.32 (m, 1H), 8.67 (d, 1H, J=4.9 Hz), 8.74 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 18 Synthesis of 4-[(2-nitrobenzene)sulfonylamino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine
Figure US06867221-20050315-C00039
4-amino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (467 mg) and 2-nitrobenzenesulfonyl chloride (244 mg) were condensed in the same manner as described in Preparation Example 10 to give the title compound.
Yield: 494 mg (91%).
PREPARATION EXAMPLE 19 Synthesis of 4-[N-(2-nitrobenzene)sulfonyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphneyl)pyridin-4-yl]methyl]piperidine
Figure US06867221-20050315-C00040
4-[(2-nitrobenzene)sulfonylamino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (494 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (267 mg) were condensed in the same manner as described in Example 2 to give the title compound.
Yield: 443 mg (61%).
EXAMPLE 5 Synthesis of 1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methylamino]piperidine difumalate
Figure US06867221-20050315-C00041
4-[N-(2-nitrobenzene)sulfonyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphneyl)pyridin-4-yl]methyl]piperidine (443 mg) was treated in the same manner as described in Preparation Example 14. The title compound was obtained after converting to a difumalate.
Yiled: 103 mg (24%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.44-1.53 (m, 2H), 1.87-1.91 (m, 2H), 2.15 (t, 2H, J=1.1 Hz), 2.57-2.64 (m, 1H), 2.82-2.85 (m, 2H), 3.59 (s, 2H), 3.78 (s, 6H), 3.89 (s, 12H), 3.90 (s, 2H), 6.63 (s, 4H), 7.24 (d, 1H, J=4.9 Hz), 7.29 (d, 1H, J=4.9 Hz), 7.35 (s, 2H), 7.37 (s, 2H), 7.76 (s, 1H), 7.85 (s, 1H), 8.53-8.56 (m, 2H).
PREPARATION EXAMPLE 20 Synthesis of 4-(ethoxycarbonylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine
Figure US06867221-20050315-C00042
To a solution of 1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine-4-carboxamide (528 mg) in a mixed solvent of ethanol (10 mL) and acetonitrile (10 mL) was added [bis(trifluoroacetoxy)iodo]benzene (884 mg). The mixture was stirred at room temperature overnight and evaporated. Saturated aqueous sodium hydrogen carbonate was added to the residue and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was applied to a column of silica gel and purified using chloroform-methanol (20:1) as an eluent to give the title compound.
Yield: 566 mg (96%). 1H-NMR (400 MHz, CDCl3) δ: 1.21 (t, 3H, J=7.0 Hz), 1.40-1.51 (m, 2H), 1.92 (d, 2H, J=10.9 Hz), 2.15 (t, 2H, J=10.9 Hz), 2.78 (d, 2H, J=11.6 Hz), 3.52 (br, 3H), 3.87 (s, 3H), 3.94 (s, 6H), 4.07 (q, 2H, J=7.0 Hz), 4.56 (br, 1H), 7.17 (d, 1H, J=4.9 Hz), 7.21 (s, 2H), 7.59 (s, 1H), 8.56 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 21 Synthesis of 4-(methylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine
Figure US06867221-20050315-C00043
To a suspension of lithium aluminum hydride (100 mg) in dry THF (50 mL) was added a solution of 4-(ethoxycarbonylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (566 mg) in dry THF (50 mL) under an argon atmosphere. The mixture was then refluxed overnight, then cooled down. Saturated aqueous ammonium chloride was added to the mixture and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was subjected to silica gel column chromatography using chloroform-ammonia saturated methanol (9:1) to give the title compound as yellow oil.
Yiled: 379 mg (78%). 1H-NMR (400 MHz, CDCl3) δ: 1.36-1.46 (m, 2H), 1.89 (d, 2H, J=12.5 Hz), 2.10 (dt, 2H, J=11.5 Hz, 1.1 Hz), 2.35-2.43 (m, 1H), 2.43 (s, 3H), 2.86 (d, 2H, J=11.6 Hz), 3.56 (s, 2H), 3.90 (s, 3H), 3.97 (s, 6H), 7.21 (d, 1H, J=5.1 Hz), 7.24 (s, 2H), 7.64 (s, 1H), 8.59(d, 1H, J=4.9 Hz).
PREPARATION EXAMPLE 22 Synthesis of 1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone ethylene ketal
Figure US06867221-20050315-C00044
4-Piperidone ethylene ketal (12.0 g) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (12.3 g) was condensed in the same manner as described in Example 2 to give the title compound.
Yield: 19.0 g (theoretical amount). 1H-NMR (400 MHz, CDCl3) δ: 1.68 (t, 4H, J=5.6 Hz), 2.48 (br, 4H), 3.50 (s, 2H), 3.82 (s, 3H), 3.86 (s, 4H), 3.88 (s, 6H), 7.13 (d, 1H, J=4.9 Hz), 7.17 (s, 2H), 7.57 (s, 1H), 8.51 (d, 1H, J=4.9 Hz).
PREPARATION EXAMPLE 23 Synthesis of 1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone
Figure US06867221-20050315-C00045
To a solution of 1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone ethylene ketal (19.0 g) in THF (200 mL) was added 1 M hydrochloric acid (200 mL). The mixture was stirred at 90° C. overnight, then neutralized with 2 M sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residual oil was applied to a column of silica gel using chloroform-methanol (40:1) as an eluent. Fractions containing the product were collected and evaporated to give the title compound.
Yield: 15.0 g (75%). 1H-NMR (400 MHz, CDCl3) δ: 2.48 (t, 4H, J=6.1 Hz), 2.79 (t, 4H, J=6.0 Hz), 3.69 (s, 2H), 3.89 (s, 3H), 3.96 (s, 6H), 7.24 (s, 2H), 7.26 (d, 1H, J=4.9 Hz), 7.66 (s, 1H), 8.62 (d, 1H, J=4.9 Hz).
PREPARATION EXAMPLE 24 Synthesis of 1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone
Figure US06867221-20050315-C00046
4-Piperidone hydrochloride monohydrate (3.07 g) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (2.94 g) were coupled by the same manner as described in Example 2 to give the title compound.
Yield: 3.55 g (99%).
PREPARATION EXAMPLE 25 Synthesis of 4-(methylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine
Figure US06867221-20050315-C00047
To a solution of 1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (1.00 g) in 1,2-dichloroethane (60 mL) was added 30% solution of methylamine in ethanol (750 mg) and sodium triacetoxyborohydride (1.66 g). The mixture was stirred at room temperature for 3 hours, then small amount of water was added and evaporated. Water was added to the residue and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was subjected to silica gel column chromatography using chloroform-methanol (40:1) to give the title compound.
Yield: 640 mg (62%).
PREPARATION EXAMPLE 26 Synthesis of ethyl 3-(3,4,5-trimethoxyphenyl)benzoate
Figure US06867221-20050315-C00048
3,4,5-Trimethoyphenylboronic acid (3.7 g) and ethyl 3-bromobenzoate (4.02 g) were condensed in the same manner as described in Preparation Example 1 to give the title compound.
Yield: 5.09 g (92%). 1H-NMR (400 MHz, CDCl3) δ: 1.42 (t, 3H, J=7.1 Hz), 3.90 (s, 3H), 3.94 (s, 6H), 4.41 (q, 2H, J=7.1 Hz), 6.79 (s, 2H), 7.50 (t, 1H, J=7.8 Hz), 7.73 (dt, 1H, J=7.1 Hz, 1.5 Hz), 8.01 (dt, 1H, J=7.8 Hz, 1.4 Hz), 8.23 (t, 1H, J=1.8 Hz).
PREPARATION EXAMPLE 27 Synthesis of 3-(3,4,5-trimethoxyphenyl)benzoic acid
Figure US06867221-20050315-C00049
Ethyl 3-(3,4,5-trimethoxyphenyl)benzoate (1.19 g) was treated in the same manner as described in Preparation Example 17 to give the title compound.
Yield: 986 mg (91%).
EXAMPLE 6 Synthesis of 4-[N-methyl-N-[3-(3,4,5-trimethoxyphenyl)]benzoylamino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine dihydrochloride
Figure US06867221-20050315-C00050
3-(3,4,5-trimethoxyphenyl)benzoic acid (1.03 g) and 4-(methylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (1.32 g) were condensed in the same method as described in Example 1. The title compound was obtained after converting a free amine to a dihydrochloride.
Yield: 1.44 g (57%). 1H-NMR (400 MHz, measured as a dihydrochloride, DMSO-d6) δ: 1.89 (d, 2H, J=11.7 Hz), 2.54-2.62 (m, 2H), 2.89 (s, 3H), 3.09 (t, 2H, J=12.7 Hz), 3.43 (d, 2H, J=14.4 Hz), 3.76 (s, 3H), 3.78 (s, 3H), 3.88 (s, 6H), 3.91 (s, 6H), 4.34 (br, 3H), 6.91 (s, 2H), 7.33 (d, 1H, J=7.6 Hz), 7.47-7.51 (m, 2H), 7.54 (s, 2H), 7.60 (s, 1H), 7.71 (d, 1H, J=7.8 Hz), 8.55 (s, 1H), 8.68 (d, 1H, J=5.1 Hz).
EXAMPLE 7 Synthesis of 4-[N-methyl-N-[[5-(3,4,5-trimethoxyphenyl)pyridin-3-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine difumarate
Figure US06867221-20050315-C00051
4-methylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (135 mg) and 3-chloromethyl-5-(3,4,5-trimethoxypyenyl)pyridine (107 mg) were condensed by the same method as described in Example 2. White powder of the title compound was obtained after converting a free base to a difumarate.
Yield: 180 mg (58%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.69-1.73 (m, 2H), 1.82-1.85 (m, 2H), 2.03-2.08 (m, 2H), 2.25 (s, 3H), 2.48-2.51 (m, 1H), 2.97-2.99 (m, 2H), 3.56 (s, 2H), 3.67 (s, 2H), 3.90 (s, 3H), 3.91 (s, 3H), 3.94 (s, 6H), 3.98 (s, 6H), 6.76 (s, 2H), 7.22 (d, 1H, J=5.1 Hz), 7.24 (s, 2H), 7.62 (s, 1H), 7.80 (s, 1H), 8.50 (d, 1H, J=2.0 Hz), 8.60 (d, 1H, J=4.3 Hz), 8.69 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 28 Synthesis of 1-bromo-4-chloro-3,5-dimethoxybenzene
Figure US06867221-20050315-C00052
A solution of sodium nitrite (97 mg) in water (2.0 mL) was added dropwise to an ice-cold suspension of 4-bromo-2,6-dimethoxyaniline (232 mg) in 6.0 M hydrochloric acid (2.5 mL). After stirring in ice for 30 minutes, a solution of cupric chloride (495 mg) in concentrated hydrochloric acid (2.0 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes, then at 100° C. for 2 hours, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate, and evaporated. The residue was subjected to a column of silica gel using hexane-ethyl acetate (10:1) as an eluent to give the title compound as white powder.
Yield: 230 mg (92%).
PREPARATION EXAMPLE 29 Synthesis of 4-chloro-3,5-dimethoxyphenylboronic acid
Figure US06867221-20050315-C00053
Under an argon atomsphere, to dry THF (2 mL) stirred in a dry ice-methanol bath was gradually added a 1.57 M solution of n-butyllithium in hexane (0.8 mL), followed by the dropwise addition of a solution of 1-bromo-4-chloro-3,5-dimethoxybenzene (160 mg) in dry THF (2 mL). After the mixture was stirred for 20 minutes in the dry ice-methanol bath, triisopropyl borate (0.18 mL) was added and the mixture was additionally stirred for 20 minutes. The reaction mixture was then stirred at room temperature for 1 hour and pH of the mixture was adjusted at 3 using 4 M hydrochloric acid. The mixture was stirred at 0° C. for 1 hour and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was recrystallized from ethyl acetate-hexane giving the title compound as white powder.
Yield: 90 mg (66%).
PREPARATION EXAMPLE 30 Synthesis of ethyl 2-(4-chloro-3,5-dimethoxyphenyl)isonicotinate
Figure US06867221-20050315-C00054
4-Chloro-3,5-dimethoxyphenylboronic acid (7.45 g) and ethyl 2-chloroisonicotinate (6.39 g) were condensedn in the same manner as described in Preparation Example 1 to give the title compound.
Yield: 8.55 g (77%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (t, 3H, J=7.3 Hz), 4.03 (s, 6H), 4.45 (q, 2H, J=7.3 Hz), 7.32 (s, 2H), 7.80 (d, 1H, J=5.1 Hz), 8.27 (s, 1H), 8.83 (d, 1H, J=5.0 Hz).
PREPARATION EXAMPLE 31 Synthesis of 2-(4-chloro-3,5-dimethoxyphenyl)isonicotinic acid
Figure US06867221-20050315-C00055
To a solution of ethyl 2-(4-chloro-3,5-dimethoxyphenyl)isonicotinate (8.55 g) in ethanol (80 mL) was added 2 M sodium hydroxide (100 mL). The mixture was refluxed for 30 min and evaporated. The aqueous layer was neutralized by 1 M hydrochloric acid and precipitates were dissolved in a mixed solvent of ethyl acetate-THF (3:1). After drying over anhydrous sodium sulfate, the solvent was evaporated to give the title compound.
Yield: 7.20 g (92%). 1H-NMR (400 MHz, CDCl3) δ: 4.02 (s, 6H), 7.34 (s, 2H), 7.83 (d, 1H, J=4.9 Hz), 7.84 (s, 1H), 8.82 (d, 1H, J=4.9 Hz).
PREPARATION EXAMPLE 32 Synthesis of 2-(4-chloro-3,5-dimethoxyphenyl)-4-hydroxymethylpyridine
Figure US06867221-20050315-C00056
To an ice-cooled solution of 2-(4-chloro-3,5-dimethoxyphenyl)isonicotinic acid (7.20 g) and triethylamine (5.6 mL) in THF (70 mL) was added ethyl chloroformate (2.8 mL). The mixture was stirred at room temperature for 1 hour and filtered. To the filtrate was then added a solution of sodium borohydride (1.25 g) in water (4 mL). The mixture was stirred at room temperature for another hour and evaporated. Water was added to the residue and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was subjected to silica gel column chromatography using chloroform-methanol (20:1) and then chloroform-methanol (15:1) to give the title compound.
Yield: 4.10 g (60%). 1H-NMR (400 MHz, CDCl3+DMSO-d6) δ: 4.01 (s, 6H), 4.76 (s, 2H), 7.20-7.35 (m, 3H), 7.78 (s, 1H), 8.62 (s,1H).
PREPARATION EXAMPLE 33 Synthesis of 2-(4-chloro-3,5-dimethoxyphenyl)-4-chloromethylpyridine
Figure US06867221-20050315-C00057
2-(4-Chloro-3,5-dimethoxyphenyl)-4-hydroxymethylpyridine (4.10 g) was treated in the same manner as described in Preparation Example 3 to give the title compound.
Yield: 4.20 g (96%). 1H-NMR (400 MHz, CDCl3) δ: 4.02 (s, 6H), 4.63 (s, 2H), 7.26 (s, 2H), 7.29 (d, 1H, J=4.9 Hz), 7.72 (s, 1H), 8.69 (d, 1H, J=4.9 Hz).
PREPARATION EXAMPLE 34 Synthesis of 1-[[2-(4-chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]piperidine-4-carboxamide
Figure US06867221-20050315-C00058
Piperidine-4-carboxamide (301 mg) and 2-(4-chloro-3,5-dimethoxyphenyl)-4-chloromethylpyridine (600 mg) were coupled in the same manner as described in Example 2 to give the title compound.
Yield: 743 mg (95%). 1H-NMR (400 MHz, CDCl3) δ: 1.75-1.90 (m, 4H), 2.07-2.25 (m, 3H), 2.94 (d, 2H, J=11.6 Hz), 3.57 (s, 2H), 4.02(s, 6H), 7.24-7.31 (m, 3H), 7.67 (s, 1H), 8.61 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 35 Synthesis of 1-[[2-(4-chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]-4-(ethoxycarbonylamino)piperidine
Figure US06867221-20050315-C00059
1-[[2-(4-chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]piperidine-4-carboxamide (743 mg) was treated in the same manner as described in Preparation Example 20 to give the title compound.
Yield: 887 mg (theoretical amount). 1H-NMR (400 MHz, CDCl3) δ: 1.24 (t, 3H, J=7.1 Hz), 1.43-1.59 (m, 2H), 1.96 (d, 2H, J=11.4 Hz), 2.19 (t, 2H, J=11.0 Hz), 2.82 (d, 2H, J=11.5 Hz), 3.56 (s, 2H), 4.02 (s, 6H), 4.10 (q, 2H, J=7.1 Hz), 7.26 (s, 2H), 7.66 (s, 1H), 7.71 (dd, 1H, J=5.6 Hz, 1.0 Hz), 8.6 (dd, 1H, J=4.9 Hz, 0.5 Hz).
PREPARATION EXAMPLE 36 Synthesis of 1-[[2-(4-chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]-4-methylaminopiperidine
Figure US06867221-20050315-C00060
1-[[2-(4-chloro-3,5-diemthoxyphenyl)pyridin-4-yl]methyl]-4-(ethoxy-carbonylamino)piperidine (887 mg) was treated in the same manner as described in Preparation Example 21 to give the title compound.
Yield: 195 mg (27%). 1H-NMR (400 MHz, CDCl3) δ: 1.35-1.49 (m, 2H), 1.89 (d, 2H, J=12.3 Hz), 2.11 (t, 2H, J=9.4 Hz), 2.38-2.45 (m, 1H), 2.44 (s, 3H), 2.87 (d, 2H, J=10.7 Hz), 3.57 (s, 2H), 4.02 (s, 6H), 7.23-7.29 (m, 3H), 7.68 (s, 1H), 8.61 (d, 1H, J=4.9 Hz).
EXAMPLE 8 Synthesis of 1-[[2-(4-chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]-4-[N-[[2-(4-chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]-N-methylamino]piperidine tetrahydrochloride
Figure US06867221-20050315-C00061
1-[[2-(4-chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]-4-methylaminopiperidine (195 mg) and 2-(4-chloro-3,5-dimethoxyphenyl)-4-chloromethylpyridine (152 mg) were condensed in the same manner as described in Example 2. A free base obtained was converted to a tetrahydrochloride giving yellow powder.
Yield: 300 mg (75%). 1H-NMR (400 MHz, CDCl3) δ: 1.60-1.90 (m, 4H), 2.06 (t, 2H, J=11.7 Hz), 2.26 (s, 3H), 2.45-2.55 (m, 1H), 2.97 (d, 2H, J=11.3 Hz), 3.57 (s, 2H), 3.67 (s, 2H), 4.01 (s, 6H), 4.02 (s, 6H), 7.24-7.28 (m, 6H), 7.65 (s, 1H), 7.67 (s, 1H), 8.61 (d, 1H, J=5.4 Hz), 8.62 (d, 1H, J=5.4 Hz).
PREPARATION EXAMPLE 37 Synthesis of 4-(p-anisidino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine
Figure US06867221-20050315-C00062
To a solution of 1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (2.17 g) in toluene (40 mL) was added p-anisidine (900 mg) and molecular sieves 4A (6.0 g). The mixture was refluxed overnight, then filtered and the filtrate was evaporated. The residual oil was dissolved in ethanol (40 mL) and sodium borohydride (276 mg) was added. The mixture was stirred at room temperature for 2 hours before concentration in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and evaporated. The residual oil was subjected to silica gel column chromatography using chloroform-methanol (50:1) to give the title compound as yellow amorphous.
Yield: 1.56 g (55%). 1H-NMR (400 MHz, CDCl3) δ: 1.48 (br, 2H), 2.05 (br, 2H), 2.20 (br, 2H), 2.86 (br, 2H), 3.23 (s, 1H), 3.58 (s, 2H), 3.74 (s, 3H), 3.91 (s, 3H), 3.97 (s, 6H), 6.58 (d, 2H, J=8.8 Hz), 6.77 (d, 2H, J=9.0 Hz), 7.22 (d, 1H, J=5.1 Hz), 7.26 (s, 2H), 7.64 (s, 1H), 8.59 (d, 1H, J=4.9 Hz).
PREPARATION EXAMPLE 38 Synthesis of ethyl 2-(3,4,5-trimethoxyphenyl)nicotinate
Figure US06867221-20050315-C00063
3,4,5-Trimethoxyphenylboronic acid (694 mg) and ethyl 2-chloronicotinate (608 mg) were reacted in the same manner as described in Preparation Example 1 to give the title compound.
Yield: 799 mg (77%). 1H-NMR (400 MHz, CDCl3) δ: 1.10 (t, 3H, J=7.2 Hz), 3.89 (s, 9H), 4.19 (q, 2H, J=7.2 Hz), 6.79 (s, 2H), 7.34 (dd, 1H, J=7.8 Hz, 4.8 Hz), 8.06 (dd, 1H, J=7.8 Hz, 1.7 Hz), 8.75 (dd, 1H, J=4.8 Hz, 1.7 Hz).
PREPARATION EXAMPLE 39 Synthesis of 3-hydroxymethyl-2-(3,4,5-trimethoxyphenyl)pyridine
Figure US06867221-20050315-C00064
Ethyl 2-(3,4,5-trimethoxyphenyl)nicotinate (468 mg) was treated in the same manner as described in Preparation Example 2 to give the title compound.
Yield: 293 mg (72%). 1H-NMR (400 MHz, CDCl3) δ: 3.90 (s, 9H), 4.72 (s, 2H), 6.83 (s, 2H), 7.32 (dd, 1H, J=7.9 Hz, 4.8 Hz), 7.92 (dd, 1H, J=7.9 Hz, 1.7 Hz), 8.62 (dd, 1H, J=4.8 Hz, 1.7 Hz).
PREPARATION EXAMPLE 40 Synthesis of 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine
Figure US06867221-20050315-C00065
3-Hydroxymethyl-2-(3,4,5-trimethoxyphenyl)pyridine (293 mg) was treated in the same manner as described in the Preparation Example 3 to give the title compound.
Yield: 311 mg (theoretical amount).
EXAMPLE 9 Synthesis of 4-[N-(4-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-3-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00066
To a solution of 4-p-anisidino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (139 mg) and 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) in acetonitrile (5 ml) was added potassium carbonate (83 mg) and potassium iodide (63 mg). The mixture was stirred at 70° C. overnight and evaporated. The residue was dissolved in chloroform, washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residual oil was applied to a column of silica gel using diethylether-metanol (20:1) as an eluent. A free base obtained was converted to a trihydrochloride to give the title compound as yellow powder.
Yield: 16 mg, (8%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.60 (br, 2H), 1.77 (br, 2H), 2.09 (br, 2H), 2.93 (br, 2H), 3.45 (br, 1H), 3.54 (s, 2H), 3.73 (s, 3H), 3.90 (s, 6H), 3.91 (s, 6H), 3.96 (s, 6H), 4.34 (s, 2H), 6.65 (d, 2H, J=9.0 Hz), 6.71 (s, 2H), 6.74 (d, 2H, J=9.0 Hz), 7.16-7.19 (m, 2H), 7.22 (s, 2H), 7.55 (s, 1H), 7.79 (d, 1H, J=7.0 Hz), 8.50 (br, 1H), 8.58 (d, 1H, J=4.9 Hz).
EXAMPLE 10 Synthesis of 4-[N-(4-methoxyphenyl)-N-[[2-(3,4,5-trimethoxypheny)pyridin-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00067
4-p-Anisidino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (1.56 g) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (1.08 g) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a trihydrochloride which gave the title compound as yellow powder.
Yield: 1.17 g (40%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.68-1.97 (m, 4H), 2.09-2.23 (m, 2H), 2.98 (br, 2H), 3.54-3.66 (m, 3H), 3.73 (s, 3H), 3.89 (s, 3H), 3.90 (s, 3H), 3.93 (s, 6H), 3.96 (s, 6H), 4.45 (s, 2H), 6.74 (d, 2H, J=9.2 Hz), 6.79 (d, 2H, J=9.2 Hz), 7.15 (s, 2H), 7.16-7.21 (m, 2H), 7.23 (s, 2H), 7.57 (s, 1H), 7.60 (s, 1H), 8.54 (d, 1H, J=5.1 Hz), 8.59 (d, 1H, J=4.9 Hz).
PREPARATION EXAMPLE 41 Synthesis of 3-(3,4,5-trimethoxyphenyl)benzyl alcohol
Figure US06867221-20050315-C00068
Ethyl 3-(3,4,5-trimethoxyphenyl)benzoate (5.09 g) was treated in the same manner as described in Preparation Example 2 to give the title compound.
Yield: 4.25 g (97%). 1H-NMR (400 MHz, CDCl3) δ: 1.87 (t, 1H, J=6.0 Hz), 3.89 (s, 3H), 3.92 (s, 6H), 4.76 (d, 1H, J=5.6 Hz), 6.77 (s, 2H), 7.34 (d, 1H, J=7.4 Hz), 7.42 (t, 1H, J=7.5 Hz), 7.48 (d, 1H, J=7.6 Hz), 7.55 (s, 1H).
PREPARATION EXAMPLE 42 Synthesis of 3-(3,4,5-trimethoxyphenyl)benzyl chloride
Figure US06867221-20050315-C00069
3-(3,4,5-Trimethoxyphenyl)benzyl alcohol (1.21 g) was treated in the same manner as described in Preparation Example 3 to give the title compound.
Yield: 893 mg (69%). 1H-NMR (400 MHz, CDCl3) δ: 3.87 (s, 3H), 3.90 (s, 6H), 4.62 (s, 2H), 6.75 (s, 2H), 7.33 (d, 1H, J=7.6 Hz), 7.39 (t, 1H, J=7.7 Hz), 7.48 (d, 1H, J=7.6 Hz), 7.54 (s, 1H).
EXAMPLE 11 Synthesis of 4-[N-(4-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine dihydrochloride
Figure US06867221-20050315-C00070
4-(p-Anisidino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (139 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a dihydrochloride which gave the title compound as yellow powder.
Yield: 52 mg (22%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.77-1.92 (m, 5H), 2.14-2.20 (m, 2H), 2.95-3.00 (m, 2H), 3.58 (s, 2H), 3.72 (s, 3H), 3.88 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 3.96 (s, 6H), 4.47 (s, 2H), 6.70 (s, 2H), 6.74-6.83 (m, 4H), 7.20 (d, 1H, J=7.4 Hz), 7.23 (s, 2H), 7.25-7.27 (m, 1H), 7.33 (t, 1H, J=7.4 Hz), 7.38 (d, 1H, J=8.7 Hz), 7.43 (s, 1H), 7.62 (s, 1H), 8.59 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 43 Synthesis of ethyl 6-(3,4,5-trimethoxyphenyl)nicotinate
Figure US06867221-20050315-C00071
3,4,5-Trimethoxyphneylboronic acid (1.16 g) and ethyl 6-chloronitotinate (1.02 g) were coupled in the same manner as described in the Preparation Example 1 to give the title compound.
Yield: 1.42 g (82%). 1H-NMR (400 MHz, CDCl3) δ: 1.43 (t, 3H, J=7.2 Hz), 3.92 (s, 3H), 3.98 (s, 6H), 4.44 (q, 2H, J=7.2 Hz), 7.32 (s, 2H), 7.76 (d, 1H, J=8.3 Hz), 8.33 (dd, 1H, J=8.2 Hz, 2.2 Hz), 9.26 (d, 1H, J=2.2 Hz).
PREPARATION EXAMPLE 44 Synthesis of 5-hydroxymethyl-2-(3,4,5-trimethoxyphenyl)pyridine
Figure US06867221-20050315-C00072
Ethyl 6-(3,4,5-trimethoxyphenyl)nicotinate (658 mg) was treated in the same manner as described in Preparation Example 2 to give the title compound.
Yield: 482 mg (85%). 1H-NMR (400 MHz, CDCl3) δ: 3.91 (s, 3H), 3.97 (s, 6H), 4.76 (s, 2H), 7.23 (s, 2H), 7.68 (d, 1H, J=7.4 Hz), 7.78 (dd, 1H, J=7.4 Hz, 2.3 Hz), 8.63 (d, 1H, J=2.3 Hz).
PREPARATION EXAMPLE 45 Synthesis of 5-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine
Figure US06867221-20050315-C00073
5-Hydroxymethyl-2-(3,4,5-trimethoxyphenyl)pyridine (685 mg) was treated in the same manner as described in Preparation Example 3 to give the title compound.
Yield: 717 mg (theoretical amount).
EXAMPLE 12 Synthesis of 4-[N-(4-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00074
4-(p-Anisidino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (139 mg) and 5-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a trihydrochloride which gave the title compound as yellow powder.
Yield: 13 mg (5%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.76 (br, 2H), 1.88 (br, 2H), 2.14 (br, 2H), 2.97 (br, 2H), 3.51 (br, 1H), 3.57 (s, 2H), 3.73 (s, 3H), 3.89 (s, 3H), 3.90 (s, 3H), 3.94 (s, 6H), 3.96 (s, 6H), 4.42 (s, 2H), 6.78 (br, 4H), 7.20 (br, 3H), 7.23 (s, 2H), 7.57-7.70 (m, 3H), 8.58-8.60 (m, 2H).
PREPARATION EXAMPLE 46 Synthesis of ethyl 5-(3,4,5-trimethoxyphenyl)nicotinate
Figure US06867221-20050315-C00075
3,4,5-Trimethoxyphenylboronic acid (6.36 g) and ethyl 5-bromonicotinate (6.90 g) were reacted in the same manner as described in Preparation Example 1 to give the title compound.
Yield: 7.19 g (76%). 1H-NMR (400 MHz, CDCl3) δ: 1.44 (t, 3H, J=7.1 Hz), 3.91 (s, 3H), 3.95 (s, 6H), 4.46 (q, 2H, J=7.1 Hz), 6.79 (s, 2H), 8.44 (t, 1H, J=2.1 Hz), 8.96 (d, 1H, J=2.1 Hz), 9.18 (d, 1H, J=1.8 Hz).
PREPARATION EXAMPLE 47 Synthesis of 3-hydroxymethyl-5-(3,4,5-trimethoxyphenyl)pyridine
Figure US06867221-20050315-C00076
Ethyl 5-(3,4,5-trimethoxyphenyl)nicotinate (7.19 g) was treated in the same manner as described in the Preparation Example 2 to give the title compound.
Yield; 3.83 g (61%). 1H-NMR (400 MHz, CDCl3) δ: 3.88 (s, 3H), 3.89 (s, 6H), 4.39 (br, 1H), 4.80 (s, 2H), 6.72 (s, 2H), 7.89 (t, 1H, J=1.2 Hz), 8.47 (d, 1H, J=2.1 Hz), 8.63 (d, 1H, J=2.2 Hz).
PREPARATION EXAMPLE 48 Synthesis of 3-chloromethyl-5-(3,4,5-trimethoxyphenyl)pyridine
Figure US06867221-20050315-C00077
3-Hydroxymethyl-5-(3,4,5-trimethoxyphenyl)pyridine (2.85 g) was treated in the same manner as described in Preparation Example 3 to give the title compound.
Yield: 1.97 g (65%). 1H-NMR (400 MHz, CDCl3) δ: 3.90 (s, 3H), 3.94 (s, 6H), 4.67 (s, 2H), 6.75 (s, 2H), 7.87 (t, 1H, J=2.1 Hz), 8.59 (d, 1H, J=2.0 Hz), 8.76 (d, 1H, J=2.1 Hz).
EXAMPLE 13 Synthesis of 4-[N-(4-methoxyphenyl)-N-[[5-(3,4,5-trimethoxyphenyl)pyridin-3-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00078
4-(p-Anisidino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (139 mg) and 3-chloromethyl-5-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a trihydrochloride which gave the title compound as yellow powder.
Yield: 14 mg (5%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ; 1.73-1.75 (m, 2H), 1.88 (d, 2H, J=11.3 Hz), 2.13 (t, 2H, J=11.3 Hz), 2.96 (d, 2H, J=11.5 Hz), 3.50 (br, 1H), 3.55 (s, 2H), 3.72 (s, 3H), 3.88 (s, 3H), 3.89 (s, 9H), 3.96 (s, 6H), 4.45 (s, 2H), 6.65 (s, 2H), 6.76 (d, 2H, J=9.6 Hz), 6.80 (d, 2H, J=9.4 Hz), 7.20 (d, 1H, J=5.3 Hz), 7.22 (s, 2H), 7.59 (s, 1H), 7.67 (s, 1H), 8.50 (s, 1H), 8.59 (d, 1H, J=4.7 Hz), 8.62 (s, 1H).
PREPARATION EXAMPLE 49 Synthesis of 2,6-dimethoxy-4-iodophenol
Figure US06867221-20050315-C00079
To a solution of 5-iodo-1,2,3-trimethoxybenzene (3.2 g) in 1,2-dichloroethane (40 mL) was added aluminum chloride (1.6 g). The mixture was stirred at 60° C. for 4 hours and evaporated. The residue was dissolved in 1 M aqueous sodium hydroxide solution and washed with ether. The aqueous layer was then acidified and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated to give the title compound as white crystalline powder.
Yield: 1.0 g (31%)
PREPARATION EXAMPLE 50 Synthesis of 1,3-dimethoxy-5-iodo-2-isopropoxybenzene
Figure US06867221-20050315-C00080
To a suspension of 2,6-dimethoxy-4-iodophenol (1.0 g) and potassium carbonate (938 mg) in DMF (10 mL) was added isopropyl iodide (507 mL). The mixture was stirred at 60° C. for 3 hours and evaporated. Ethyl acetate and water were added to the residue, the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was applied to a column of silica gel using hexane-ethyl acetate (5:1) as an eluent to give the title compound.
Yield: 788 mg (72%).
PREPARATION EXAMPLE 51 Synthesis of 3,5-dimethoxy-4-isopropoxyphenylboronic acid
Figure US06867221-20050315-C00081
1,3-Dimethoxy-5-iodo-2-isopropoxybenzene (2.25 g) was treated in the same manner as described in Preparation Example 27 to give the title compound.
Yield: 1.23 g (74%).
PREPARATION EXAMPLE 52 Synthesis of ethyl 2-(3,5-dimethoxy-4-isopropoxyphenyl)isonicotinate
Figure US06867221-20050315-C00082
To a solution of 3,5-dimethoxy-4-isopropoxyphenylboronic acid (1.23 g) and ethyl 2-chloroisonicotinate (0.95 g) were condensed in the same manner as described in Preparation Example 1 to give the title compound.
Yield: 1.57 g(89%). 1H-NMR (400 MHz, CDCl3) δ: 1.33 (d, 6H, J=4.9 Hz), 1.44 (t, 3H, J=7.1 Hz), 3.95 (s, 6H), 4.42-4.49 (m, 3H), 7.29 (s, 2H), 7.75 (dd, 1H, J=4.9 Hz, 1.4 Hz), 8.24 (s, 1H), 8.80 (d, 1H, J=4.9 Hz).
PREPARATION EXAMPLE 53 Synthesis of 2-(3,5-dimethoxy-4-isopropoxyphenyl)-4-hydroxymethylpyridine
Figure US06867221-20050315-C00083
Ethyl 2-(3,5-dimethoxy -4-isopropoxyphenyl)isonicotinate (1.57 g) was treated in the same manner as described in the Preparation Example 2 to give the title compound.
Yield: 1.27 g (92%). 1H-NMR (400 MHz, CDCl3) δ: 1.32 (d, 6H, J=6.1 Hz), 3.93 (s, 6H), 4.45 (quint, 1H, J=6.1 Hz), 4.81 (s, 2H), 7.20 (d, 1H, J=5.1 Hz), 7.23 (s, 2H), 7.68 (s, 1H), 8.62 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 54 Synthesis of 4-chloromethyl-2-(3,5-dimethoxy-4-isopropoxyphenyl)pyridine
Figure US06867221-20050315-C00084
2-(3,5-Dimethoxy-4-isopropoxyphenyl)-4-hydroxymethylpyridine (1.49 g) was treated in the same manner as described in Preparation Example 3 to give the title compound.
Yield: 1.33 g (84%). 1H-NMR (400 MHz, CDCl3) δ: 1.32 (d, 6H, J=6.2 Hz), 3.94 (s, 6H), 4.45 (quint, 1H, J=6.1 Hz), 4.61 (s, 2H), 7.23-7.26 (m, 3H), 7.69 (s, 1H), 8.66 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 55 Synthesis of 1-[[2-(3,5-dimethoxy-4-isopropoxyphenyl)pyridin-4-yl]methyl]-4-piperidone ethylene ketal
Figure US06867221-20050315-C00085
4-Chloromethyl-2-(3,5-dimethoxy-4-isopropoxyphenyl)pyridine (643 mg) and 4-piperidone ethylene ketal (287 mg) were coupled in the same manner as described in Example 2 to give the title compound.
Yield: 818 mg (95%). 1H-NMR (400 MHz, CDCl3) δ: 1.32 (d, 6H, J=6.1 Hz), 1.78 (t, 4H, J=5.7 Hz), 2,57 (br, 4H), 3.49 (s, 4H), 3.59 (s, 2H), 3.94 (s, 6H), 4.44 (quint, 1H, J=6.1 Hz), 7.21 (d, 1H, J=5.1 Hz), 7.23 (s, 2H), 7.65 (s, 1H), 8.59 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 56 Synthesis of 1-[[2-(3,5-dimethoxy-4-isopropoxyphenyl)pyridin-4-yl]methyl]-4-piperidone
Figure US06867221-20050315-C00086
1-[[2-(3,5-Dimethoxy-4-isopropoxyphenyl)pyridin-4-yl]methyl]-4-piperidone ethylene ketal (818 mg) was treated in the same manner as described in Preparation Example 23 to give the title compound.
Yield: 717 mg (98%). 1H-NMR (400 MHz, CDCl3) δ: 1.32 (d, 6H, J=6.2 Hz), 2.50 (t, 4H, J=6.1 Hz), 2.81 (t, 4H, J=6.1 Hz), 3.69 (s, 2H), 3.95 (s, 6H), 4.45 (quint, 1H, J=6.2 Hz), 7.24 (s, 2H), 7.25-7.27 (m, 1H), 7.68 (s, 1H), 8.63 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 57 Synthesis of 4-(p-anisidino)-1-[[2-(3,5-dimethoxy-4-isopropoxyphenyl)pyridin -4-yl]methyl]piperidine
Figure US06867221-20050315-C00087
1-[[2-(3,5-dimethoxy-4-isopropoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (350 mg) and p-anisidine (123 mg) were condensed in the same manner as described in Preparation Example 37 to give the title compound.
Yield: 307 mg (69%). 1H-NMR (400 MHz, CDCl3) δ: 1.32 (d, 6H, J=6.3 Hz), 1.46-1.52 (m, 2H), 2.00-2.24 (m, 2H), 2.22 (t, 2H, J=11.1 Hz), 2.86 (d, 2H, J=12.1 Hz), 3.18-3.28 (m, 1H), 3.58 (s, 2H), 3.74 (s, 3H), 3.94 (s, 6H), 4.40 (quint, 1H, J=6.3 Hz), 6.58 (d, 2H, J=6.6 Hz), 6.78 (d, 2H, J=6.6 Hz), 7.20 (d, 1H, J=5.1 Hz), 7.24 (s, 2H), 7.64 (s, 1H), 8.59 (d, 1H, J=5.1 Hz).
EXAMPLE 14 Synthesis of 1-[[2-(3,5-dimethoxy-4-isopropoxyphenyl)pyridin-4-yl]methyl]-4-[N-[[2-(3,5-dimethoxy-4-isopropoxyphenyl)pyridin-4-yl]methyl]-N-(4-methoxyphenyl) amino]piperidine trihydrochloride
Figure US06867221-20050315-C00088
4-p-anisidino)-1-[[2-(3,5-dimethoxy-4-isopropoxyphenyl)pyridin-4-yl]methyl]piperidine (307 mg) and 4-chloromethyl-2-(3,5-dimethoxy-4-isopropoxyphenyl) pyridine (201 mg) were condensed in the same manner as described in Example 9. A free base obtained was converted to a trihydrochloride giving the title compound as yellow powder.
Yield: 230 mg (46%). 1H-NMR (400 MHz, CDCl3) δ: 1.31 (d, 6H, J=3.3 Hz), 1.32 (d, 6H, J=6.8 Hz), 1.70-1.92 (m, 4H), 2.10-2.20 (m, 2H), 2.92-3.01 (m, 2H), 3.56 (s, 2H), 3.73 (s, 3H), 3.85-3.95 (m, 1H), 3.90 (s, 6H), 3.93 (s, 6H), 4.39-4.49 (m, 4H), 6.73 (d, 2H, J=4.8 Hz), 6.78 (d, 2H, J=4.8 Hz), 7.14 (s, 2H), 7.15-7.20 (m, 2H), 7.23 (s, 2H), 7.58 (s, 1H), 7.60 (s, 1H), 8.53 (d, 1H, J=5.1 Hz), 8.58 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 58 Synthesis of 4-benzylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]-methyl]piperidine
Figure US06867221-20050315-C00089
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl-4-piperidone (1.40 g) and benzylamine (0.51 g) was condensed in the same manner as described in Preparation Example 37 to give the title compound as yellow amorphous.
Yield: 1.20 g (68%). 1H-NMR (400 MHz, CDCl3) δ: 1.40-1.60 (m, 2H), 1.88-2.09 (m, 5H), 2.54 (br, 1H), 2.82-2.85 (m, 2H), 3.52 (s, 2H), 3.80 (s, 2H), 3.89 (s, 3H), 3.95 (s, 6H), 7.18-7.31 (m, 8H), 7.64 (s, 1H), 8.57 (d, 1H, J=5.1 Hz).
EXAMPLE 15 Synthesis of 4-[N-benzyl-N-[[2-(3,4,5-trimethoxypheny)pyridin-3-yl]-methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine tetrahydrochloride
Figure US06867221-20050315-C00090
4-Benzylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (134 mg) and 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed in the same manner as described in Example 9. A free base obtained was converted to a tetrahydrochloride to give the title compound as yellow powder.
Yield: 43 mg, (17%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.63 (br, 4H), 1.87 (br, 2H), 2.39 (br, 1H), 2.88 (br, 2H), 3.49 (s, 2H), 3.57 (s, 2H), 3.68 (s, 2H), 3.86 (s, 6H), 3.88 (s, 3H), 3.90 (s, 3H), 3.96 (s, 6H), 6.60 (s, 2H), 7.17 (d, 1H, J=5.1 Hz), 7.22-7.29 (m, 8H), 7.56 (s, 1H), 8.02 (d, 1H, J=8.0 Hz), 8.50 (d, 1H, J=6.4 Hz), 8.58 (d, 1H, J=5.1 Hz).
EXAMPLE 16 Synthesis of 4-[N-benzyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine tetrahydrochloride
Figure US06867221-20050315-C00091
4-Benzylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (230 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (158 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a tetrahydrochloride which gave the title compound as yellow powder.
Yield: 172 mg (47%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.69-1.85 (m, 4H), 1.93-1.99 (m, 2H), 2.56 (br, 1H), 2.93-3.00 (m, 2H), 3.51 (s, 2H), 3.71 (s, 2H), 3.74 (s, 2H), 3.90 (s, 6H), 3.96 (s, 6H), 7.18-7.32 (m, 9H), 7.38 (d, 2H, J=7.1 Hz), 7.59 (s, 1H), 7.68 (s, 1H), 8.56 (d, 1H, J=5.1 Hz), 8.60 (d, 1H, J=5.1 Hz).
EXAMPLE 17 Synthesis of 4-[N-benzyl-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00092
4-Benzylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (134 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a trihydrochloride which gave the title compound as yellow powder.
Yield: 47 mg (18%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.70-1.86 (m, 4H), 1.96 (br, 2H), 2.59 (br, 1H), 2.94 (br, 2H), 3.51 (s, 2H), 3.70 (s, 2H), 3.74 (s, 2H), 3.89 (s, 3H), 3.90 (s, 3H), 3.92 (s, 6H), 3.96 (s, 6H), 6.75 (s, 2H), 7.18-7.30 (m, 6H), 7.35-7.40 (m, 5H), 7.56 (s, 1H), 7.60 (s, 1H), 8.58 (d, 1H, J=5.1 Hz).
EXAMPLE 18 Synthesis of 4-[N-benzyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine tetrahydrochloride
Figure US06867221-20050315-C00093
4-Benzylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (134 mg) and 5-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a tetrahydrochloride which gave the title compound as yellow powder.
Yield: 44 mg (17%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.81 (br, 4H), 1.96 (br, 2H), 2.55 (br, 1H), 2.96 (br, 2H), 3.52 (s, 2H), 3.69 (s, 4H), 3.89 (s, 6H), 3.95 (s, 6H), 3.96 (s, 6H), 7.19-7.32 (m, 8H), 7.36-7.38 (m, 2H), 7.61 (d, 2H, J=7.6 Hz), 7.69-7.73 (m, 1H), 8.59 (d, 1H, J=4.9 Hz), 8.63 (s, 1H).
EXAMPLE 19 Synthesis of 4-[N-benzyl-N-[[5-(3,4,5-trimethoxypheny)pyridin-3-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine tetrahydrochloride
Figure US06867221-20050315-C00094
4-Benzylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (134 mg) and 3-chloromethyl-5-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a tetrahydrochloride which gave the title compound as yellow powder.
Yield: 26 mg (10%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.83 (br, 4H), 1.97 (br, 2H), 2.58 (br, 1H), 2.95 (br, 2H), 3.53 (s, 2H), 3.71 (s, 2H), 3.75 (s, 2H), 3.90 (s, 6H), 3.93 (s, 6H), 3.96 (s, 6H), 6.74 (s, 2H), 7.19-7.30 (m, 6H), 7.36 (d, 2H, J=6.8 Hz), 7.60 (s, 1H), 7.79 (s, 1H), 8.54 (s, 1H), 8.59 (d, 1H, J=5.1 Hz), 8.64 (s, 1H).
PREPARATION EXAMPLE 59 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[[2-(3,4,5-trmethoxyphenyl)pyridin-4-yl]methyl]aminomethyl]piperidine
Figure US06867221-20050315-C00095
1-(tert-Butoxycarbonyl)-4-aminomethylpiperidine (200 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (183 mg) were condensed in the same manner as described in Example 2 to give the title compound as yellow syrup.
Yield: 264 mg (90%). 1H-NMR (400 MHz, CDCl3) δ: 1.12-1.27 (m, 3H), 1.45 (s, 9H), 1.60 (br, 1H), 1.74 (d, 2H, J=12.9 Hz), 2.54 (d, 2H, J=6.6 Hz), 2.69 (br, 2H), 3.87 (s, 2H), 3.90 (s, 3H), 3.97 (s, 6H), 4.03-4.14 (m, 2H), 7.20 (d, 1H, J=3.9 Hz), 7.24 (s, 2H), 7.65 (s, 1H), 8.60 (d, 1H, J=4.9 Hz).
PREPARATION EXAMPLE 60 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl) pyridin-4-yl]methyl]aminomethyl]piperidine
Figure US06867221-20050315-C00096
1-(tert-butoxycarbonyl)-4-[N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]aminomethyl]piperidine (264 mg) was treated in the same manner as described in Preparation Example 11 to give the title compound as yellow syrup.
Yield: 157 mg (58%). 1H-NMR (400 MHz, CDCl3) δ: 1.00-1.09 (m, 2H), 1.43 (s, 9H), 1.65-1.70 (m, 1H), 1.79 (d, 2H, J=12.7 Hz), 2.21 (d, 2H, J=7.4 Hz), 2.23 (s, 3H), 2.69 (br, 2H), 3.52 (s, 2H), 3.89 (s, 3H), 3.96 (s, 6H), 4.07-4.13 (m, 2H), 7.20 (d, 1H, J=4.9 Hz), 7.24 (s, 2H), 7.64 (s, 1H), 8.58 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 61 Synthesis of 4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]aminomethyl]piperidine
Figure US06867221-20050315-C00097
1-(tert-Butoxycarbonyl)-4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]aminomethyl]piperidine (152 mg) was treated in the same manner as described in Preparation Example 12 to give the title compound as yellow crystals.
Yield: 105 mg (88%). 1H-NMR (400 MHz, CDCl3) δ: 1.00-1.10 (m, 2H), 1.60-1.68 (m, 1H), 1.80 (d, 2H, J=12.5 Hz), 2.03 (br, 1H), 2.20 (d, 2H, J=8.4 Hz), 2.21 (s, 3H), 2.58 (dt, 2H, J=12.1 Hz, 2.1 Hz), 3.05 (d, 2H, J=12.1 Hz), 3.51 (s, 2H), 3.89 (s, 3H), 3.95 (s, 6H), 7.20 (d, 1H, J=5.1 Hz), 7.24 (s, 2H), 7.65 (s, 1H), 8.57 (d, 1H, J=5.9 Hz).
EXAMPLE 20 Synthesis of 4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]aminomethyl]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine dioxalate
Figure US06867221-20050315-C00098
4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino-methyl] piperidine (96 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (73 mg) were condensed in the same manner as described in Example 2. The title compound was obtained as white powder after converting a free base to a dioxalate.
Yield: 109 mg (40%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.19-1.27 (m, 2H), 1.56 (br, 1H), 1.81 (d, 2H, J=11.1 Hz), 1.99-2.04 (m, 2H), 2.23 (s, 5H), 2.88 (d, 2H, J=11.1 Hz), 3.53 (s, 4H), 3.89 (s, 3H), 3.90 (s, 3H), 3.94 (s, 6H), 3.96 (s, 6H), 7.20 (br, 2H), 7.23 (s, 4H), 7.61 (s, 1H), 7.64 (s, 1H), 8.58 (d, 2H, J=4.9 Hz).
PREPARATION EXAMPLE 62 Synthesis of 4-(3,5-dimethoxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine
Figure US06867221-20050315-C00099
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl-4-piperidone (1.40 g) and 3,5-dimethoxyaniline (722 mg) were treated in the same manner as described in Preparation Example 37 to give the title compound.
Yield: 800 mg (41%). 1H-NMR (400 MHz, CDCl3) δ: 1.40-1.90 (m, 2H), 1.95-2.50 (m, 4H), 2.93 (br, 2H), 3.31 (br, 1H), 3.65 (br, 2H), 3.72 (s, 6H), 3.88 (s, 3H), 3.96 (s, 6H), 5.76 (s, 2H), 5.85 (s, 1H), 7.20-7.35 (m, 3H), 7.73 (br, 1H), 8.60 (d, 1H, J=4.9 Hz).
EXAMPLE 21 Synthesis of 4-[N-(3,5-dimethoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-3-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00100
4-(3,5-Dimethoxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (148 mg) and 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed in the same manner as described in Example 9. Yellow syrup obtained was converted to a trihydrochloroide to give the title compound as yellow powder.
Yield: 29 mg, (11%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.60-1.63 (m, 2H), 1.79 (d, 2H, J=11.7 Hz), 2.13 (t, 2H, J=11.4 Hz), 2.94 (d, 2H, J=11.3 Hz), 3.54 (s, 2H), 3.71 (s, 6H), 3.78-3.84 (m, 1H), 3.90 (s, 3H), 3.91 (s, 6H), 3.92 (s, 3H), 3.96 (s, 6H), 4.41 (s, 2H), 5.84 (s, 2H), 6.72 (s, 2H), 7.09-7.24 (m, 5H), 7.53 (s, 1H), 7.71 (d, 1H, J=6.6 Hz), 8.51 (dd, 1H, J=4.7 Hz, 1.6 Hz), 8.59 (d, 1H, J=4.9 Hz).
PREPARATION EXAMPLE 63 Synthesis of ethyl 2-(3,4,5-trimethoxyphenyl)benzoate
Figure US06867221-20050315-C00101
3,4,5-Trimethoxyphenylboronic acid (639 mg) and ethyl 2-bromobenzoate (479 mg) were condensed in the same manner as described in Preparation Example 1 to give the title compound.
Yield: 655 mg (69%). 1H-NMR (400 MHz, CDCl3) δ: 1.04 (t, 3H, J=7.2 Hz), 3.86 (s, 6H), 3.89 (s, 3H), 4.12 (q, 2H, J=7.2 Hz), 6.54 (s, 2H), 7.40-7.42 (m, 2H), 7.51 (t, 1H, J=7.8 Hz), 7.77 (d, 1H, J=6.8 Hz).
PREPARATION EXAMPLE 64 Synthesis of 2-(3,4,5-trimethoxyphenyl)benzyl alcohol
Figure US06867221-20050315-C00102
Ethyl 2-(3,4,5-trimethoxyphenyl)benzoate (655 mg) was treated in the same manner as described in Preparation Example 2 to give the title compound.
Yield: 630 mg (theoretical amount). 1H-NMR (400 MHz, CDCl3) δ: 3.85 (s, 6H), 3.90 (s, 3H), 4.61 (s, 2H), 6.61 (s, 2H), 7.26-7.39 (m, 3H), 7.53 (d, 1H, J=6.8 Hz).
PREPARATION EXAMPLE 65 Synthesis of 2-(3,4,5-trimethoxyphneyl)benzyl chloride
Figure US06867221-20050315-C00103
2-(3,4,5-Trimethoxyphenyl)benzyl alcohol (630 mg) was treated in the same manner as described in Preparation Example 3 to give the title compound.
Yield: 615 mg (theoretical amount). 1H-NMR (400 MHz, CDCl3) δ: 3.87 (s, 6H), 3.90 (s, 3H), 4.53 (s, 2H), 6.66 (s, 2H), 7.29-7.32 (m, 1H), 7.34-7.39 (m, 2H), 7.50-7.52 (m, 1H).
EXAMPLE 22 Synthesis of 4-[N-(3,5-dimethoxyphenyl)-N-[2-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine dihydrochloride
Figure US06867221-20050315-C00104
4-(3,5-Dimethoxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (148 mg) and 2-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed in the same manner as described in Example 9. A free base obtained was converted to a dihydrochloroide to give the title compound as yellow powder.
Yield: 20 mg, (8%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.50-1.90 (m, 4H), 2.05-2.20 (m, 2H), 2.92 (br, 2H), 3.52 (br, 3H), 3.68 (s, 6H), 3.85 (s, 6H), 3.88 (s, 3H), 3.89 (s, 3H), 3.94 (s, 6H), 4.31 (s, 2H), 5.85 (br, 3H), 6.52 (s, 2H), 7.05-7.27 (m, 6H), 7.34 (s, 1H), 7.51 (s, 1H), 8.56 (s, 1H).
EXAMPLE 23 Synthesis of 4-[N-(3,5-dimethoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00105
4-(3,5-Dimethoxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (148 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a trihydrochloride which gave the title compound as yellow powder.
Yield: 40 mg (18%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.68-1.90 (m, 4H), 2.12-2.22 (m, 2H), 2.94-3.02 (m, 2H), 3.57 (s, 2H), 3.71 (s, 6H), 3.81-3.83 (m, 1H), 3.89 (s, 3H), 3.90 (s, 3H), 3.93 (s, 6H), 3.96 (s, 6H), 4.52 (s, 2H), 5.89-5.94 (m, 3H), 7.14 (d, 1H, J=5.3 Hz), 7.16 (s, 2H), 7.20 (d, 1H, J=3.7 Hz), 7.22 (s, 2H), 7.54-7.60 (m, 2H), 8.55 (d, 1H, J=5.1 Hz), 8.59 (d, 1H, J=5.1 Hz).
EXAMPLE 24 Synthesis of 4-[N-(3,5-dimethoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine dihydrochloride
Figure US06867221-20050315-C00106
4-(3,5-Dimethoxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (148 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a dihydrochloride which gave the title compound as yellow powder.
Yield: 41 mg (16%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.78-1.88 (m, 4H), 2.16 (t, 2H, J=10.7 Hz), 2.96 (d, 2H, J=11.3 Hz), 3.56 (s, 2H), 3.70 (s, 6H), 3.73-3.84 (m, 1H), 3.87 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 3.95 (s, 6H), 4.54 (s, 2H), 5.95 (s, 2H), 6.71 (s, 2H), 7.19-7.26 (m, 4H), 7.31-7.39 (m, 3H), 7.42 (s, 1H), 7.59 (s, 1H), 8.58 (d, 1H, J=4.9 Hz).
EXAMPLE 25 Synthesis of 4-[N-(3,5-dimethoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00107
4-(3,5-Dimethoxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (148 mg) and 5-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a trihydrochloride which gave the title compound as yellow powder.
Yield: 23 mg (10%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.64 (br, 2H), 1.82 (br, 2H), 2.10 (br, 2H), 2.94 (br, 2H), 3.48-3.60 (m, 3H), 3.64 (s, 6H), 3.82 (s, 3H), 3.83 (s, 3H), 3.87 (s, 6H), 3.90 (s, 6H), 4.46 (s, 2H), 5.85 (br, 3H), 7.05-7.24 (m, 6H), 7.53-7.54 (m, 2H), 8.51 (s, 1H), 8.54 (br, 1H).
PREPARATION EXAMPLE 66 Synthesis of ethyl 4-(3,4,5-trimethoxyphenyl)benzoate
Figure US06867221-20050315-C00108
3,4,5-Trimethoxyphenylboronic acid (2.01 g) and ethyl 4-bromobenzoate (2.29 g) were condensed in the same manner as described in Preparation Example 1 to give the title compound.
Yield: 2.99 g (95%). 1H-NMR (400 MHz, CDCl3) δ: 1.42 (t, 3H, J=7.2 Hz), 3.90 (s, 3H), 3.94 (s, 6H), 4.38 (q, 2H, J=7.2 Hz), 6.81 (s, 2H), 7.62 (d, 2H, J=8.2 Hz), 8.10 (d, 2H, J=8.2 Hz).
PREPARATION EXAMPLE 67 Synthesis of 4-(3,4,5-trimethoxyphenyl)benzyl alcohol
Figure US06867221-20050315-C00109
Ethyl 4-(3,4,5-trimethoxyphenyl)benzoate (2.99 g) was treated in the same manner as described in Preparation Example 2 to give the title compound.
Yield: 1.83 g (71%)
PREPARATION EXAMPLE 68 Synthesis of 4-(3,4,5-trimethoxyphenyl)benzyl chloride
Figure US06867221-20050315-C00110
4-(3,4,5-Trimethoxyphenyl)benzyl alcohol (1.83 g) was treated in the same manner as describe in Preparation Example 3 to give the title compound.
Yield: 1.65 g (84%) 1H-NMR (400 MHz, CDCl3) δ: 3.90 (s, 3H), 3.93 (s, 6H), 4.65 (s, 2H), 6.77 (s, 2H), 7.46 (d, 2H, J=8.0 Hz), 7.55 (d, 2H, J=8.0 Hz).
EXAMPLE 26 Synthesis of 4-[N-(3,5-dimethoxyphenyl)-N-[4-(3,4,5-trimethoxypheny)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine dihydrochloride
Figure US06867221-20050315-C00111
4-(3,5-Dimethoxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (148 mg) and 4-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a dihydrochloride which gave yellow powder of the title compound.
Yield: 35 mg (14%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ; 1.80-1.89 (m, 4H), 2.17 (br, 2H), 2.97 (d, 2H, J=10.5 Hz), 3.57 (s, 2H), 3.70 (s, 6H), 3.77-3.84 (m, 1H), 3.87 (s, 3H), 3.90 (s, 3H), 3.91 (s, 6H), 3.96 (s, 6H), 4.52 (s, 2H), 5.93 (s, 2H), 6.74 (s, 2H), 7.19-7.22 (m, 4H), 7.31 (d, 2H, J=8.2 Hz), 7.46 (d, 2H, J=8.2 Hz), 7.60 (s, 1H), 8.59 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 69 Synthesis of 4-(3,4-methylenedioxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl) pyridin-4-yl]methyl]piperidine
Figure US06867221-20050315-C00112
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl-4-piperidone (1.40 g) and 3,4-methylenedioxyaniline (646 mg) were treated in the same manner as described in Preparation Example 29 to give the title compound.
Yield: 810 mg (43%). 1H-NMR (400 MHz, CDCl3) δ: 1.63 (br, 2H), 2.02-2.60 (m, 4H), 2.80-3.15 (m, 2H), 3.25 (br, 1H), 3.70 (br, 2H), 3.88 (s, 3H), 3.96 (s, 6H), 5.83 (s, 2H), 6.02 (d, 1H, J=8.3 Hz), 6.22 (s, 1H), 6.61 (d, 1H, J=8.3 Hz), 7.18-7.28 (m, 3H), 7.64 (br, 1H), 8.60 (d, 1H, J=4.9 Hz).
EXAMPLE 27 Synthesis of 4-[N-(3,4-methylenedioxyphenyl)-N-[[2-(3,4,5-trimethoxypheny) pyridin-3-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00113
4-(3,4-Methylenedioxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (119 mg) and 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed in the same manner as described in Example 9. Yellow syrup obtained was converted to a trihydrochloroide to give the title compound as yellow powder.
Yield: 30 mg (14%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.45-2.25 (m, 6H), 2.90 (br, 2H), 3.40 (br, 1H), 3.55 (br, 2H), 3.87 (s, 3H), 3.88 (s, 9H), 3.93 (s, 6H), 4.28 (s, 2H), 5.82 (s, 2H), 6.10 (br, 1H), 6.28 (s, 1H), 6.58 (d, 1H, J=8.4 Hz), 6.67 (s, 2H), 7.12-7.30 (m, 4H), 7.52 (br, 1H), 7.75 (br, 1H), 8.51 (br, 1H), 8.57 (br, 1H).
EXAMPLE 28 Synthesis of 4-[N-(3,4-methylenedioxyphenyl)-N-[2-(3,4,5-trimethoxyphenyl) benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]metyl]piperidine dihydrochloride
Figure US06867221-20050315-C00114
4-(3,4-Methylenedioxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (119 mg) and 2-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed in the same manner as described in Example 9. A free base obtained was converted to a dihydrochloroide to give the title compound as yellow powder.
Yield: 13 mg (6%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.61 (br, 2H), 1.78 (br, 2H), 2.10 (br, 2H), 2.91 (br, 2H), 3.50-3.54 (m, 3H), 3.87 (s, 6H), 3.90 (s, 3H), 3.92 (s, 3H), 3.99 (s, 6H), 4.26 (s, 2H), 5.82 (s, 2H), 6.12 (d, 1H, J=8.6 Hz), 6.32 (s, 1H), 6.53 (s, 2H), 6.62 (d, 1H, J=8.6 Hz), 7.17-7.26 (m, 6H), 7.42 (br, 1H), 7.55 (s, 1H), 8.58 (d, 1H, J=4.9 Hz).
EXAMPLE 29 Synthesis of 4-[N-(3,4-methylenedioxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl) pyridin-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00115
4-(3,4-Methylenedioxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (119 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl) pyridine (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a trihydrochloride which gave the title compound as yellow powder.
Yield: 52 mg (25%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.60-1.95 (m, 4H), 2.20 (br, 2H), 3.00 (br, 2H), 3.58 (br, 3H), 3.86 (s, 3H), 3.87 (s, 3H), 3.91 (s, 6H), 3.94 (s, 6H), 4.41 (s, 2H), 5.82 (s, 2H), 6.17 (d, 1H, J=8.4 Hz), 6.39 (s, 1H), 6.62 (d, 1H, J=8.4 Hz), 7.12-7.13 (m, 3H), 7.18 (d, 1H, J=4.1 Hz), 7.23 (br, 2H), 7.54 (br, 2H), 8.51 (d, 1H, J=5.1 Hz), 8.57 (d, 1H, J=4.9 Hz).
EXAMPLE 30 Synthesis of 4-[N-(3,4-methylenedioxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl) benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine dihydrochloride
Figure US06867221-20050315-C00116
4-(3,4-Methylenedioxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (119 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a dihydrochloride which gave the title compound as yellow powder.
Yield: 58 mg (29%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.60-1.97 (m, 4H), 2.15 (br, 2H), 3.00 (br, 2H), 3.58 (br, 3H), 3.86 (s, 3H), 3.88 (s, 9H), 3.94 (s, 6H), 4.43 (s, 2H), 5.81 (s, 2H), 6.21 (br, 1H), 6.42 (s, 1H), 6.62 (d, 1H, J=8.4 Hz), 6.69 (s, 2H), 7.18 (d, 1H, J=4.9 Hz), 7.22-7.39 (m, 6H), 7.60 (br, 1H), 8.57 (d, 1H, J=4.9 Hz).
EXAMPLE 31 Synthesis of 4-[N-(3,4-methylenedioxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl) pyridin-5-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00117
4-(3,4-Methylenedioxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (119 mg) and 5-chloromethyl-2-(3,4,5-trimethoxyphenyl) pyridine (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a trihydrochloride which gave the title compound as yellow powder.
Yield: 69 mg (27%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.71-1.88 (m, 4H), 2.14 (d, 2H, J=11.2 Hz), 2.97 (d, 2H, J=11.5 Hz), 3.45-3.52 (m, 1H), 3.56 (s, 2H), 3.89 (s, 3H), 3.90 (s, 3H), 3.94 (s, 6H), 3.96 (s, 6H), 4.12 (s, 2H), 5.85 (s, 2H), 6.24 (dd, 1H, J=8.5 Hz, 2.5 Hz), 6.45 (d, 1H, J=2.4 Hz), 6.64 (d, 1H, J=8.5 Hz), 7.20-7.21 (m, 1H), 7.21 (s, 2H), 7.23 (s, 2H), 7.58-7.65 (m, 3H), 8.57 (d, 1H, J=1.5 Hz), 8.59 (d, 1H, J=4.9 Hz).
EXAMPLE 32 Synthesis of 4-[N-(3,4-Methylenedioxyphenyl)-N-[4-(3,4,5-trimethoxyphenyl) benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine dihydrochloride
Figure US06867221-20050315-C00118
4-(3,4-Methylenedioxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (119 mg) and 4-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a dihydrochloride which gave the title compound as yellow powder.
Yield: 29 mg (14%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ; 1.62-2.00 (m, 4H), 2.20 (br, 2H), 2.99 (br, 2H), 3.58 (br, 3H), 3.86 (s, 3H), 3.87 (s, 3H), 3.88 (s, 6H), 3.89 (s, 6H), 4.41 (s, 2H), 5.82 (s, 2H), 6.19 (d, 1H, J=8.6 Hz), 6.39 (s, 1H), 6.63 (d, 1H, J=8.4 Hz), 6.72 (s, 2H), 7.18 (d, 1H, J=5.1 Hz), 7.23 (s, 2H), 7.29 (d, 2H, J=8.0 Hz), 7.43 (d, 2H, J=8.2 Hz), 7.60 (br, 1H), 8.57 (d, 1H, J=4.9 Hz).
PREPARATION EXAMPLE 70 Synthesis of 4-[N-methyl-N-[(2-nitrobenzene)sulfonyl]aminomethyl]-2-(3,4,5-trimethoxyphenyl)pyridine
Figure US06867221-20050315-C00119
4-Chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (232 mg), N-methyl-2-nitrobenzenesulfonamide (171 mg) and potassium carbonate (138 mg) were suspended in acetonitrile (10 mL). The mixture was stirred at room temperature overnight and evaporated. To the residue was added chloroform and water. The organic layer was separated, washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and evaporated to give the title compound.
Yield: 362 mg (97.0%).
PREPARATION EXAMPLE 71 Synthesis of 4-(methylaminomethyl)-2-(3,4,5-trimethoxyphenyl)pyridine
Figure US06867221-20050315-C00120
To a suspension of 4-[N-methyl-N-[(2-nitrobenzene)sulfonyl]aminomethyl]-2-(3,4,5-trimethoxyphenyl)pyridine (691 mg) and potassium carbonate (203 mg) in acetonitrile (20 mL) was added thiophenol (228 μL). The mixture was stirred at 50° C. overnight and evaporated. To the residue was added chloroform and water. The organic layer was separated, washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to a column of silica gel using chloroform-methanol (40:1) and then chloroform-methanol (10:1) as eluents. Fractions containing the product were collected and evaporated to give the title compound.
Yield: 356 mg (84%).
EXAMPLE 33 Synthesis of 4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]aminocarbonyl]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine maleate
Figure US06867221-20050315-C00121
1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine-4-caroxylic acid (98 mg) and 4-(methylaminomethyl)-2-(3,4,5-trimethoxyphenyl)pyridine (73 mg) were condensed by the same manner as described in Example 1 giving a maleate of the title compound as white powder.
Yield: 145 mg (75%). 1H-NMR (400 MHz, measured as a maleate, DMSO-d6) δ: 1.89-1.97 (m, 4H), 2.75-2.96 (m, 3H), 3.03 (s, 3H), 3.27 (d, 2H, J=12.0 Hz), 3.78 (s, 3H), 3.79 (s, 3H), 3.87 (s, 6H), 3.90 (s, 6H), 4.09 (s, 2H), 4.64 (s, 2H), 6.14 (s, 2H), 7.09 (d, 1H, J=5.0 Hz), 7.33 (s, 2H), 7.37 (d, 1H, J=5.0 Hz), 7.38 (s, 2H), 7.65 (s, 1H), 7.90 (s, 1H), 8.57 (d, 1H, J=5.0 Hz), 8.67 (d, 1H, J=5.0 Hz).
PREPARATION EXAMPLE 72 Synthesis of (3S)-1-(tert-butoxycarbonyl)-3-[N-[(2-nitrobenzene)sulfonyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]pyrrolidine
Figure US06867221-20050315-C00122
(3S)-1-(tert-Butoxycarbonyl)-3-[(2-nitrobenzene)sulfonylamino]pyrrolidine (72 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (57 mg) were condensed in the same manner as described in Example 2 to give colorless amorphous of the title compound.
Yield:103 mg (85%).
PREPARATION EXAMPLE 73 Synthesis of (3S)-3-[N-[(2-nitrobenzene)sulfonyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]pyrrolidine
Figure US06867221-20050315-C00123
(3S)-1-(tert-butoxycarbonyl)-3-[N-[(2-nitrobenzene)sulfonyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]pyrrolidine (103 mg) was treated in the same manner as described in Preparation Example 12 to give yellow amorphous of the title compound.
Yield: 72 mg (84%). 1H-NMR (400 MHz, CDCl3) δ: 1.66-1.75 (m, 1H), 2.03-2.05 (m, 1H), 2.78-2.85 (m, 2H), 3.00-3.10 (m, 2H), 3.39 (br, 1H), 3.90 (s, 3H), 3.96 (s, 6H), 4.59-4.67 (m, 1H), 4.70 (s, 2H), 7.13-7.18 (m, 1H), 7.20 (s, 2H), 7.52-7.64 (m, 4H), 7.95 (dd, 1H, J=7.9 Hz, 1.1 Hz), 8.52 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 74 Synthesis of (3S)-3-[N-[(2-nitrobenzene)sulfonyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]pyrrolidine
Figure US06867221-20050315-C00124
(3S)-3-[N-[(2-Nitrobenzene)sulfonyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]pyrrolidine (72 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (40 mg) were treated in the same manner as described in Example 2 to give a yellow amorphous of the title compound.
Yield: 97 mg (91%). 1H-NMR (400 MHz, CDCl3) δ: 1.59 (br, 1H), 1.80-1.90 (m, 1H), 2.20-2.30 (m, 2H), 2.55 (dd, 1H, J=10.5 Hz, 8.2 Hz), 2.78 (dd, 1H, J=10.6 Hz, 3.2 Hz), 2.87 (t, 1H, J=7.2 Hz), 3.50 (d, 1H, J=13.7 Hz), 3.64 (d, 1H, J=13.7 Hz), 3.89 (s, 3H), 3.90 (s, 3H), 3.92 (s, 6H), 3.93 (s, 6H), 4.83 (d, 2H, J=4.5 Hz), 7.07 (d, 1H, J=5.1 Hz), 7.10 (d, 1H, J=4.9 Hz), 7.15 (s, 2H), 7.17 (s, 2H), 7.41-7.45 (m, 1H), 7.50-7.55 (m, 3H), 7.61 (s, 1H), 7.81 (d, 1H, J=7.4 Hz), 8.45 (d, 1H, J=4.9 Hz), 8.51(d, 1H, J=5.1 Hz).
EXAMPLE 34 Synthesis of (3S)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-3-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methylamino]pyrrolidine trihydrochloride
Figure US06867221-20050315-C00125
(3S)-3-[N-[(2-nitrobenzene)sulfonyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]pyrrolidine (97 mg) was treated in the same manner as described in Preparation Example 11 to give yellow amorphous of the title compound, which was converted to a trihydrochloride.
Yield: 80 mg (89%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.71(br, 2H), 2.19-2.21 (m, 1H), 2.52-2.55 (m, 2H), 2.73-2.77 (m, 2H), 3.39 (br, 1H), 3.66 (d, 1H, J=13.7 Hz), 3.71 (d, 1H, J=13.7 Hz), 3.82 (s, 2H), 3.90 (s, 6H), 3.95 (s, 12H), 7.18-7.21 (m, 2H), 7.23 (s, 2H), 7.24 (s, 2H), 7.63 (s, 2H), 8.59 (d, 1H, J=4.3 Hz), 8.60 (d, 1H, J=4.3 Hz).
EXAMPLE 35 Synthesis of 4-[3-(3,4,5-trimethoxyphenyl)benzoylamino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine maleate
Figure US06867221-20050315-C00126
3-(3,4,5-trimethoxyphenyl)benzoic acid (69 mg) and 4-amino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (114 mg) were condensed in the same manner as described in Example 1. The title compound was obtained after converting the product to a maleate.
Yield: 100 mg (56%). 1H-NMR (400 MHz, measured as a maleate, DMSO-d6) δ: 1.85-2.10 (m, 4H), 2.77-2.93 (m, 2H), 3.20-3.31 (m, 2H), 3.77 (s, 3H), 3.79(s, 3H), 3.89 (s, 6H), 3.91 (s, 6H), 3.984.07 (m, 1H), 4.13 (s, 2H), 6.15 (s, 2H), 6.94 (s, 2H), 7.40-7.52 (m, 4H), 7.73-7.80 (m, 2H), 8.02-8.10 (m, 3H), 8.67-8.68 (m, 1H).
EXAMPLE 36 Synthesis of 4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine tetrahydrochloride
Figure US06867221-20050315-C00127
4-(methylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (2.67 g) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (2.12 g) were condensed in the same manner as described in Example 2. The title compound was obtained after converting a free base to a tetrahydrochloride.
Yield: 2.55 g (46%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.66-1.74 (m, 2H), 1.82 (d, 2H, J=10.7 Hz), 2.04 (t, 2H, J=11.0 Hz), 2.25 (s, 3H), 2.45-2.51 (m, 1H), 2.98 (d, 2H, J=11.7 Hz), 3.55 (s, 2H), 3.66 (s, 2H), 3.90 (s, 3H), 3.91 (s, 3H), 3.96 (s, 6H), 3.97 (s, 6H), 7.21-7.23 (m, 2H), 7.24 (s, 2H), 7.25 (s, 2H), 7.62 (s, 1H), 7.63 (s, 1H), 8.59 (d, 1H, J=5.1 Hz), 8.60 (d, 1H, J=5.3 Hz).
PREPARATION EXAMPLE 75 Synthesis of 1-(ethoxycarbonyl)-4-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methylamino]piperidine
Figure US06867221-20050315-C00128
4-Amino-1-(ethoxycarbonyl)piperidine (341 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (300 mg) were condensed in the same manner as described in Example 2 to give the title compound.
Yield: 438 mg (theoretical yield). 1H-NMR (400 MHz, CDCl3) δ: 1.25 (t, 3H, J=7.1 Hz), 1.27-1.34 (m, 2H), 1.60 (br, 1H), 1.90 (d, 2H, J=10.9 Hz), 2.67-2.72 (m, 1H), 2.87 (t, 2H, J=11.5 Hz), 3.90 (s, 3H), 3.91 (br, 2H), 3.96 (s, 6H), 4.09 (br, 2H), 4.12 (q, 2H, J=7.0 Hz), 7.21 (d, 1H, J=3.5 Hz), 7.24 (s, 2H), 7.65 (s, 1H), 8.59 (d, 1H, J=4.9 Hz).
PREPARATION EXAMPLE 76 Synthesis of 1-(ethoxycarbonyl)-4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00129
To a solution of 1-(ethoxycarbonyl)-4-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methylamino]piperidine (438 mg) was treated in the same manner as described in Preparation Example 11 to give the title compound as yellow syrup.
Yield: 235 mg (52%). 1H-NMR (400 MHz, CDCl3) δ: 1.26 (t, 3H, J=7.1 Hz), 1.42-1.57 (m, 2H), 1.82 (d, 2H, J=11.9 Hz), 2.24 (s, 3H), 2.59-2.65 (m, 1H), 2.75 (t, 2H, J=12.0 Hz), 3.65 (s, 2H), 3.90 (s, 3H), 3.97 (s, 6H), 4.13 (q, 2H, J=7.0 Hz), 4.23 (br, 2H), 7.22 (dd, 1H, J=5.0 Hz, 1.3 Hz), 7.24 (s, 2H), 7.63 (s, 1H), 8.59 (d, 1H, J=4.5 Hz).
PREPARATION EXAMPLE 77 Synthesis of 4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00130
To a solution of 1-(ethoxycarbonyl)-4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine (100 mg) in ethanol (2 mL) was added 4 M sodium hydroxide (8 mL). The mixture was refluxed overnight and extracted with chloroform. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was subjected to a column of silica gel and liquid chromatography was performed using chloroform-methanol (20:1) to give the title compound as yellow syrup.
Yield: 73 mg (88%). 1H-NMR (400 MHz, CDCl3) δ: 1.50-1.55 (m, 2H), 1.84 (d, 2H, J=12.0 Hz), 1.99 (br, 1H), 2.25 (s, 3H), 2.55-2.63 (m, 3H), 3.16 (d, 2H, J=12.2 Hz), 3.65 (s, 2H), 3.90 (s, 3H), 3.97 (s, 6H), 7.22 (d, 1H, J=6.1 Hz), 7.24 (s, 2H), 7.64 (s, 1H), 8.58 (d, 1H, J=5.1 Hz).
EXAMPLE 37 Synthesis of 4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine tetrahydrochloride
Figure US06867221-20050315-C00131
4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine (73 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (58 mg) were condensed in the same manner as described in Example 2. The title compound was obtained after converting a free base to a tetrahydrochloride.
Yield: 126 mg (84%).
EXAMPLE 38 Synthesis of 4-[N-methyl-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine difumarate
Figure US06867221-20050315-C00132
4-(methylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (111 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (88 mg) were condensed in the same manner as described in Example 2. The title compound was obtained as white powder after converting a free base to a difumarate.
Yield: 59 mg (46%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.70-1.77 (m, 2H), 1.85-1.87 (m, 2H), 2.03-2.08 (m, 2H), 2.27 (s, 3H), 2.55-2.59 (m, 1H), 2.98 (d, 2H, J=11.3 Hz), 3.56 (s, 2H), 3.69 (s, 2H), 3.89 (s, 3H), 3.90 (s, 3H), 3.93 (s, 6H), 3.98 (s, 6H), 6.79 (s, 2H), 7.22 (d, 1H, J=4.9 Hz), 7.28 (s, 2H), 7.31 (d, 1H, J=7.6 Hz), 7.38 (t, 1H, J=7.4 Hz), 7.45 (d, 1H, J=7.6 Hz), 7.51 (s, 1H), 7.63 (s, 1H), 8.60 (d. 1H, J=5.1 Hz).
EXAMPLE 39 Synthesis of 4-[N-methyl-N-[[2-(3,5-dimethoxy-4-hydroxyphenyl)pyridin-4-yl]methyl]amino]-1-[[2-(3,5-dimethoxy-4-hydroxyphenyl)pyridin-4-yl]methyl]piperidine tetrahydrochloride
Figure US06867221-20050315-C00133
To an ice-cooled solution of 4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (100 mg) in dichloromethane (5 mL) was added iodotrimethylsilane (173 μL). The mixture was stirred at 0° C. for 2 hours and then at room temperature overnight. A small amount of water, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added to the mixture at 0° C. and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was applied to a preparative TLC using chloroform-ammonia saturated methanol (15:1) to give a free base of the title compound which was converted to a tetrahydrochloride by the conventional method.
Yield: 50 mg (52.3%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.68-1.89 (m, 4H), 2.03-2.12 (m, 2H), 2.26 (s, 3H), 2.48-2.60 (m, 1H), 2.98-3.05 (m, 2H), 3.57 (s, 2H), 3.65 (s, 2H), 3.94 (s, 6H), 3.95 (s, 6H), 7.16-7.19 (m, 2H), 7.26 (s, 2H), 7.27 (s, 2H), 7.62-7.68 (m, 2H), 8.56 (d, 1H, J=5.3 Hz), 8.58 (d, 1H, J=5.2 Hz).
PREPARATION EXAMPLE 78 Synthesis of 1-(ethoxycarbonyl)-4-[N-ethyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00134
To a solution of 1-(ethoxycarbonyl)-4-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methylamino]piperidine (400 mg) in acetonitrile (5 mL) was added potassium carbonate (13 mg) and iodoethane (145 mg). The mixture was placed in sealed vessel and stirred at 80° C. for 2 hours. After removing the solvent in vacuo, ethyl acetate was added, washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was subjected to a column of silica gel using chloroform-methanol (30:1) as an eluent. Fractions containing the product were collected and evaporated to give the title compound as yellow syrup.
Yield: 242 mg (57%). 1H-NMR (400 MHz, CDCl3) δ: 1.04 (t, 3H, J=7.1 Hz), 1.25 (t, 3H, J=7.1 Hz),1.43-1.52 (m, 2H), 1.79 (d, 2H, J=11.5 Hz), 2.60 (q, 2H, J=7.0 Hz), 2.66-2.76 (m, 3H), 3.70 (s, 2H), 3.90 (s, 3H), 3.97 (s, 6H), 4.12 (q, 2H, J=7.0 Hz), 4.20 (br, 2H), 7.23 (s, 2H), 7.26 (d, 1H, J=5.7 Hz), 7.67 (s, 1H), 8.58 (d, 1H, J =4.9 Hz).
PREPARATION EXAMPLE 79 Synthesis of 4-[N-ethyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00135
1-(ethoxycarbonyl)-4-[N-ethyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine (242 mg) was treated in the same manner as described in Preparation Example 77 to give the title compound as yellow syrup.
Yield: 150 mg (74%). 1H-NMR (400 MHz, CDCl3) δ: 1.03 (t, 3H, J=7.0 Hz), 1.43-1.52 (m, 2H),1.70 (br, 1H), 1.79 (d, 2H, J=12.3 Hz), 2.53-2.67 (m, 5H), 3.13 (d, 2H, J=11.9 Hz), 3.71 (s, 2H), 3.90 (s, 3H), 3.97 (s, 6H), 7.24 (s, 2H), 7.27 (d, 1H, J=5.1 Hz), 7.68 (s, 1H), 8.57 (d, 1H, J=4.3 Hz).
EXAMPLE 40 Synthesis of 4-[N-ethyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine tetrahydrochloride
Figure US06867221-20050315-C00136
4-[N-ethyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine (65 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (50 mg) were condensed in the same manner as described in Example 2. The title compound was obtained after converting a free base to a tetrahydrochloride.
Yield: 121 mg (90%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.03 (t, 3H, J=7.1 Hz), 1.641.69 (m, 2H), 1.77 (d, 2H, J=10.7 Hz), 2.01 (t, 2H, J=10.8 Hz), 2.55-2.64 (m, 3H), 2.95 (d, 2H, J=11.1 Hz), 3.53 (s, 2H), 3.71 (s, 2H), 3.90 (s, 6H), 3.97 (s, 12H), 7.20-7.27 (m, 6H), 7.60 (s, 1H), 7.68 (s, 1H), 8.57 (d, 1H, J=4.9 Hz), 8.59 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 80 Synthesis of 4-(cyclohexylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine
Figure US06867221-20050315-C00137
1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-pieridone (400 mg) and cyclohexylamine (134 mg) were reacted in the same manner as described in Preparation Example 37 to give the title compound.
Yield: 342 mg (69%). 1H-NMR (400 MHz, CDCl3) δ: 1.05-1.30 (m, 6H), 1.38-1.52 (m, 2H), 1.53-1.80 (m, 3H), 1.87 (br, 4H), 2.07 (t, 2H, J=10.7 Hz), 2.59(br, 2H), 2.86 (br, 2H), 3.5 (s, 2H), 3.90 (s, 3H), 3.97 (s, 6H), 7.19 (d, 1H, J=4.9 Hz), 7.24 (s, 2H), 7.64 (s, 1H), 8.58 (d, 1H, J=4.9 Hz).
EXAMPLE 41 Synthesis of 4-[N-cyclohexyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine tetrahydrochloride
Figure US06867221-20050315-C00138
4-(Cyclohexylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (342 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (252 mg) were reacted in the same manner as described in Preparation Example 6. The title compound was obtained after converting the product to a tetrahydrochloride.
Yield: 55 mg (8%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.00-1.39 (m, 6H),1.58-1.88 (m, 8H), 2.07 (br, 2H), 2.61(br, 2H), 2.96 (br, 2H), 3.57 (br, 2H), 3.85 (s, 2H), 3.90 (s, 3H), 3.91 (s, 3H), 3.97 (s, 12H), 7.19-7.28 (m, 6H), 7.70 (br, 2H), 8.56 (d, 1H, J=5.1 Hz), 8.60 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 81 Synthesis of 4-anilino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine
Figure US06867221-20050315-C00139
1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (1.1 g) and aniline (344 mg) were reacted in the same manner as described in Preparation Example 37 to give the title compound.
Yield: 1.09 g (81%). 1H-NMR (400 MHz, CDCl3) δ: 1.53 (br, 2H), 2.02-2.13 (m, 2H), 2.16-2.32 (m, 2H), 2.86 (br, 2H), 3.32 (br, 1H), 3.59 (s, 2H), 3.88 (s, 3H), 3.95 (s, 6H), 6.57 (d, 2H, J=8.6 Hz), 6.66 (t, 1H, J=7.3 Hz), 7.14 (t, 2H, =7.9 Hz), 7.20-7.24 (m, 5H), 7.65 (br, 1H), 8.59 (d, 1H, J=5.1 Hz).
EXAMPLE 42 Synthesis of 4-[N-phenyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00140
4-Anilino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (1.64 g) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (1.64 g) were reacted in the same manner as described in Preparation Example 9. The title compound was obtained after converting the product to a trihydrochloride.
Yield: 635 mg (20%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.60-2.00 (m, 4H), 2.10-2.35 (m, 2H), 2.99 (br, 2H), 3.58 (br, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 3.90 (s, 6H), 3.94 (s, 6H), 4.52 (s, 2H), 6.66-6.78 (m, 3H), 7.13-7.28 (m, SH), 7.54 (br, 2H), 8.53 (d, 1H, J=5.1 Hz), 8.58 (d, 1H, J=4.9 Hz).
PREPARATION EXAMPLE 82 Synthesis of 1-[[2-(4-chloro-3,5-dimethoxy)phenylpyridin-4-yl]methyl]-4-piperidone ethylene ketal
Figure US06867221-20050315-C00141
4-Piperidone ethylene ketal (573 mg) and 2-(4-chloro-3,5-dimetoxyphenyl)-4-chloromethylpyridine (1.19 g) were condensed in the same manner as described in Example 2 to give the title compound.
Yield: 1.67 g (theoretical amount). 1H-NMR (400 MHz, CDCl3) δ: 1.78 (t, 4H, J=5.6 Hz), 2.58 (br, 4H), 3.61 (s, 2H), 3.67 (s, 4H), 4.02 (s, 6H), 7.25-7.29 (m, 3H), 7.68 (s, 1H), 8.61 (d, 1H, J=4.9 Hz).
PREPARATION EXAMPLE 83 Synthesis of 1-[[2-(4-chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone
Figure US06867221-20050315-C00142
1-[[2-(4-Chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone ethylene ketal (1.67 g) was treated in the same manner as described in Preparation Example 23 to give the title compound.
Yield: 1.29 g (89%). 1H-NMR (400 MHz, CDCl3) δ: 2.50 (t, 4H, J=5.8 Hz), 2.81 (t, 4H, J=5.8 Hz), 3.71 (s, 2H), 4.02 (s, 6H), 7.26 (s, 2H), 7.33 (d, 1H, J=4.3 Hz), 7.70 (s, 1H), 8.66 (d, 1H, J=4.9 Hz).
PREPARATION EXAMPLE 84 Synthesis of 4-anilino-1-[[2-(4-chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]piperidine
Figure US06867221-20050315-C00143
1-[[2-(4-Chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (600 mg) and aniline (0.18 mL) were reacted in the same manner as described in Preparation Example 37 to give the title compound.
Yield: 465 mg (63%). 1H-NMR (400 MHz, CDCl3) δ: 1.49-1.69 (m, 2H), 2.08 (d, 2H, J=7.8 Hz), 2.23 (t, 2H, J=9.3 Hz), 2.87 (d, 2H, J=7.8 Hz), 3.34 (br, 1H), 3.60 (s, 2H), 4.02 (s, 6H), 6.60 (d, 2H), J=7.6 Hz), 6.69 (t, 1H, J=7.3 Hz), 7.10-7.20 (m, 2H), 7.20-7.30 (m, 3H), 7.67 (s, 1H), 8.62 (d, 1H, J=5.2 Hz).
EXAMPLE 43 Synthesis of 1-[[2-(4-chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]-4-[N-[[2-(4-chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]-N-phenylamino]piperidine trihydrochloride
Figure US06867221-20050315-C00144
4-Anilino-1-[[2-(4-chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]piperidine (230 mg) and 2-(4-chloro-3,5-dimethoxyphenyl)-4-chloromethylpyridine (157 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a trihydrochloride.
Yield: 104 mg (24%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.70-1.85 (m, 4H), 2.20 (t, 2H, J=2.3 Hz), 3.00 (d, 2H, J=1.3 Hz), 3.59 (s, 2H), 3.96 (s, 6H), 4.00 (s, 6H), 4.56 (s, 2H), 6.65-6.78 (m, 3H), 7.16 (s, 2H), 7.18-7.28 (m, 6H), 7.59 (s, 1H), 7.62 (s, 1H), 8.57 (d, 1H), J=5.1 Hz), 8.57 (d, 1H, J=4.8 Hz).
PREPARATION EXAMPLE 85 Synthesis of 4-(p-anisidino)-1-[[2-(4-chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]piperidine
Figure US06867221-20050315-C00145
1-[[2-(4-Chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (690 mg) and p-anisidine (283 mg) were reacted in the same manner as described in Preparation Example 37 to give the title compound.
Yield: 646 mg (72%). 1H-NMR (400 MHz, CDCl3) δ: 1.45-1.55 (m, 2H), 2.05 (d, 2H, J=11.7 Hz), 2.20 (t, 2H, J=11.2 Hz), 2.87 (d, 2H, J=11.7 Hz), 3.20-3.35 (m, 1H), 3.59 (s, 2H), 3.74 (s, 3H), 4.02 (s, 6H), 6.58 (d, 2H, J=8.7 Hz), 6.77 (d, 2H, J=8.7 Hz), 7.25-7.28 (m, 3H), 7.67 (s, 1H), 8.62 (d, 1H, J=4.9 Hz).
EXAMPLE 44 Synthesis of 1-[[2-(4-chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]-4-[N-[[2-(4-chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]-N-(4-methoxyphenyl)amino]piperidine trihydrochloride
Figure US06867221-20050315-C00146
4-(p-Anisidino)-1-[[2-(4-chloro-3,5-dimethoxyphenyl)pyridin-4-yl]methyl]piperidine (271 mg) and 2-(4-chloro-3,5-dimethoxyphenyl)-4-chloromethylpyridine (173 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a trihydrochloride.
Yield: 324 mg (67%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.65-1.90 (m, 4H), 2.16 (t, 2H, J=10.4 Hz), 2.97 (d, 2H, J=7.5 Hz), 3.54-3.60 (m, 1H), 3.58 (s, 2H), 3.73 (s, 3H), 3.97 (s, 6H), 4.00 (s, 6H), 4.46 (s, 2H), 6.74 (d, 2H, J=9.4 Hz), 6.79 (d, 2H, J=9.4 Hz), 7.16 (s, 2H), 7.20-7.29 (m, 4H), 7.59 (s, 1H), 7.62 (s, 1H), 8.56 (d, 1H, J=4.8 Hz), 8.60 (d, 1H, J=4.8 Hz).
PREPARATION EXAMPLE 86 Synthesis of 4-(3-methylthioanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine
Figure US06867221-20050315-C00147
1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (1.40 g) and 3-methylthioaniline (655 mg) were reacted in the same manner as described in Preparation Example 37 to give the title compound.
Yield: 1.01 g (54%). 1H-NMR (400 MHz, CDCl3) δ: 1.44-1.60 (m, 2H), 1.98-2.10 (m, 2H), 2.23 (br, 2H), 2.42 (s, 3H), 2.88 (br, 2H), 3.30 (br, 1H), 3.59 (s, 2H), 3.88 (s, 3H), 3.95 (s, 6H), 6.35 (d, 1H), J=7.6 Hz), 6.47 (s, 1H), 6.55 (d, 1H, J=8.6 Hz), 7.05 (t, 1H, J=7.9 Hz), 7.20 (d, 1H, J=4.9 Hz), 7.24 (s, 2H), 7.68 (br, 1H), 8.58 (d, 1H, J=4.9 Hz).
EXAMPLE 45 Synthesis of 4-[N-(3-methylthiophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-3-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00148
4-(3-Methylthioanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (143 mg) and 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a trihydrochloride.
Yield: 45 mg (18%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.58-1.71 (s, 2H),1.79 (d, 2H, J=10.7 Hz), 2.16 (t, 2H, J=11.2 Hz), 2.38 (s, 3H), 2.96 (d, 2H, J=11.2 Hz), 3.56 (s, 3H), 3.68-3.97 (m, 1H), 3.90 (s, 3H), 3.92 (s, 9H), 3.96 (s, 9H), 4.42 (s, 2H), 6.45 (d, 1H, J=8.3 Hz), 6.52 (s, 1H), 6.61 (d, 1H, J=7.3 Hz), 6.74 (s, 2H), 7.11 (t, 1H, J=8.1 Hz), 7.15-7.26 (m, 4H), 7.54 (s, 1H), 7.68 (d, 1H, J=7.8 Hz), 8.53 (d, 1H, J=3.2 Hz), 8.59 (d, 1H, J=4.8 Hz).
EXAMPLE 46 Synthesis of 4-[N-(3-methylthiophenyl)-N-[2-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine dihydrochloride
Figure US06867221-20050315-C00149
4-(3-Methylthioanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (143 mg) and 2-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a dihydrochloride.
Yield: 51 mg (23%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.56-1.73 (m, 2H), 1.78-1.87 (m, 2H), 2.10-2.20 (m, 2H), 2.38 (s, 3H), 2.91-2.98 (m, 2H), 3.55 (s, 2H), 3.70-3.80 (m, 1H), 3.88 (s, 6H), 3.90 (s, 3H), 3.92 (s, 3H), 3.96 (s, 6H), 4.35 (s, 2H), 6.47 (d, 1H, J=8.2 Hz), 6.53-6.62 (m, SH), 7.09 (t, 1H, J=8.0 Hz), 7.18-7.40 (m, 6H), 7.54 (s, 1H), 8.58 (d, 1H, J=4.7 Hz).
EXAMPLE 47 Synthesis of 4-[N-(3-methylthiophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine fumarate
Figure US06867221-20050315-C00150
4-(3-Methylthioanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (143 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as white powder after converting a free base to a fumarate.
Yield: 14 mg (5%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.76-1.86 (m, 5H), 2.17-2.23 (m, 2H), 2.39 (s, 3H), 2.97-3.00 (m, 2H), 3.58 (s, 2H), 3.89 (s, 3H), 3.90 (s, 3H), 3.93 (s, 6H), 3.96 (s, 6H), 4.54 (s, 2H), 6.47-6.50 (m, 1H), 6.63 (s, 1H), 6.64 (s, 1H), 7.10-7.15 (m, 2H), 7.15 (s, 2H), 7.20-7.21 (m, 1H), 7.22 (s, 2H), 7.55 (s, 1H), 7.59 (s, 1H), 8.56 (d, 1 H), J=5.1 Hz), 8.59 (d, 1 H, J=5.1 Hz).
EXAMPLE 48 Synthesis of 4-[N-(3-methylthiophenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine dihydrochloride
Figure US06867221-20050315-C00151
4-(3-Methylthioanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (143 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a dihydrochloride.
Yield: 60 mg (24%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.65-1.91 (m, 4H), 2.18 (t, 2H, J=10.5 Hz), 2.38 (s, 3H), 2.97 (d, 2H, J=10.9 Hz), 3.58 (s, 2H), 3.70-3.85 (m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 3.96 (s, 6H), 4.56 (s, 2H), 6.52 (d, 1H, J=8.4 Hz), 6.59 (d, 1H, J=7.6 Hz), 6.65 (s, 1H), 6.72 (s, 2H), 7.10 (t, 2H, J=8.0 Hz), 7.19-7.25 (m, 4H), 7.31-7.42 (m, 3H), 7.60 (s, 1H), 8.59 (d, 1H, J=7.8 Hz).
EXAMPLE 49 Synthesis of 4-[N-(3-methylthiophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00152
4-(3-Methylthioanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (143 mg) and 5-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a trihydrochloride.
Yield: 22 mg (9%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.50-2.05 (m, 4H), 2.20 (br, 2H), 2.37 (s, 3H), 3.05 (br, 2H), 3.50-3.70 (br, 3H), 3.86 (s, 3H), 3.87 (s, 3H), 3.92 (s, 6H), 3.95 (s, 6H), 4.52 (s, 2H), 6.49 (d, 1H, J=8.3 Hz), 6.62 (br, 2H), 7.09 (t, 1H, J=8.2 Hz), 7.18-7.30 (m, 6H), 7.58 (s, 2H), 8.54 (br 1H), 8.60 (br, 1H).
EXAMPLE 50 Synthesis of 4-[N-(3-methyithiophenyl)-N-[4-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine dihydrochloride
Figure US06867221-20050315-C00153
4-(3-Methylthioanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (143 mg) and 4-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a dihydrochloride.
Yield: 57 mg (22%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.58-1.83 (m, 4H), 2.20 (t, 2H, J=11.3 Hz), 2.39 (s, 3H), 2.98 (d, 2H, J=11.1 Hz), 3.58 (s, 2H), 3.88 (s, 3H), 3.90 (s, 3H), 3.91 (s, 6H), 3.96 (s, 6H), 4.53 (s, 2H), 6.51 (dd, 1H, J=8.4 Hz, 2.4 Hz), 6.60 (d, 1H, J=8.0 Hz), 6.64 (s, 1H), 6.75 (s, 2H), 7.10 (t, 1H, J=8.1 Hz), 7.24-7.33 (m, 4H), 7.47 (d, 2H, J=8.0 Hz), 7.61 (s, 1H), 8.59 (d, 1H, J=5.0 Hz).
PREPARATION EXAMPLE 87 Synthesis of 4-propargylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine
Figure US06867221-20050315-C00154
1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (400 mg) and propargylamine (80 mg) were reacted in the same manner as described in Preparation Example 25 to give the title compound.
Yield: 227 mg (63%). 1H-NMR (400 MHz, CDCl3) δ: 1.38-1.51 (m, 2H), 1.83-1.86 (m, 3H), 2.10-2.15 (m, 2H), 2.21 (s, 1H), 2.74 (br, 1H), 2.83-2.87 (m, 2H), 3.45 (s, 2H), 3.56 (s, 2H), 3.89 (s, 3H), 3.96 (s, 6H), 7.19 (d, 1H, J=4.9 Hz), 7.24 (s, 2H), 7.65 (s, 1H), 8.58 (d, 1H, J=4.9 Hz).
EXAMPLE 51 Synthesis of 4-[N-propargyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine tetrahydrochloride
Figure US06867221-20050315-C00155
4-Propargylamino-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (227 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (226 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a tetrahydrochloride.
Yield: 128 mg (23%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.48-2.40 (m, 7H), 2.72 (br, 1H), 3.02 (br, 2H), 3.39 (s, 2H), 3.64 (br, 2H), 3.84 (s, 2H), 3.91 (s, 6H), 3.98 (s, 6H), 3.99 (s, 6H), 7.22-7.29 (m, 6H), 7.66 (br, 2H), 8.60 (d, 1H, J=4.9 Hz), 8.62 (d, 1H, J=4.9 Hz).
PREPARATION EXAMPLE 88 Synthesis of 4-(5-indanylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine
Figure US06867221-20050315-C00156
1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (1.40 g) and 5-aminoindan (680 mg) were reacted in the same manner as described in Preparation Example 37 to give the title compound.
Yield: 1.22 g (59%). 1H-NMR (400 MHz, CDCl3) δ: 1.40-1.57 (m, 2H), 2.00-2.15 (m, 5H), 2.19-2.25 (m, 2H), 2.77-2.93 (m, 6H), 3.30 (br, 1H), 3.58 (s, 2H), 3.91 (s, 3H), 3.97 (s, 6H), 6.41 (d, 1H, J=8.0 Hz), 6.52 (s. 1H), 7.01(d. 1H, J=8.0 Hz), 7.21-7.26 (m, 3H), 7.64 (s, 1H), 8.60 (d, 1H, J=4.9 Hz).
EXAMPLE 52 Synthesis of 4-[N-(indan-5-yl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-3-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00157
4-(5-Indanylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (142 mg) and 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a trihydrochloride.
Yield: 90 mg (41%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.54-1.67 (m, 2H), 1.74-1.83 (m, 2H), 1.98-2.07 (m, 2H), 2.09-2.98 (m, 2H), 3.55 (s, 2H), 3.64-3.74 (m, 1H), 3.90 (s, 3H), 3.91 (s, 6H), 3.92 (s, 3H), 3.96 (s, 6H), 4.41 (s, 2H), 6.49 (dd, 1H, J=8.2 Hz, 2.4 Hz), 6.59 (s, 1H), 6.74 (s, 2H), 7.04 (d, 1H, J=8.2 Hz), 7.15-7.20 (m, 2H), 7.22 (s, 2H), 7.54 (s, 1H), 7.77 (dd, 1H, J=7.8 Hz, 1.4 Hz), 8.52 (dd, 1H, J=4.7 Hz, 1.8 Hz), 8.59 (d, 1H, J=5.1 Hz).
EXAMPLE 53 Synthesis of 4-[N-(indan-5-yl)-N-[2-(3,4,5-trimethoxyphenyl)benzyl]amino]1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine dihydrochloride
Figure US06867221-20050315-C00158
4-(5-Indanylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (142 mg) and 2-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a dibydrochloride.
Yield: 115 mg (47%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.56-1.66 (m, 2H), 1.80-1.83 (m, 2H), 2.00-2.05 (m, 2H), 2.11-2.18 (m, 2H), 2.77-2.83 (m, 4H), 2.92-2.95 (m, 2H), 3.55 (s, 2H), 3.72 (br, 1H), 3.87 (s, 6H), 3.90 (s, 3H), 3.92 (s, 3H), 3.96 (s, 6H), 4.34 (s, 2H), 6.49 (d, 1H, J=8.3 Hz), 6.56 (s, 2H), 6.60 (s, 1H), 7.02 (d, 1H, J=8.3 Hz), 7.17-7.27 (m, 5H), 7.42-7.45 (m, 1H), 7.54 (s, 1H), 8.58 (d, 1H, J=4.9 Hz).
EXAMPLE 54 Synthesis of 4-[N-(indan-5-yl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00159
4-(5-Indanylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (142 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as white powder after converting a free base to a trihydrochloride.
Yield: 23 mg (9%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.60-1.95 (m, 4H), 2.00 (quint, 2H, J=7.3 Hz), 2.20 (br, 2H), 2.75-2.81 (m, 4H), 2.99 (br, 2H), 3.58 (br, 2H), 3.77 (s, 1H), 3.86 (s, 3H), 3.87 (s, 3H), 3.91 (s, 6H), 3.94 (s, 6H), 4.49 (s, 2H), 6.51 (d, 1H, J=8.3 Hz), 6.62 (s, 1H), 7.02 (d, 1H, J=8.0 Hz), 7.16 (s, 2H), 7.18-7.22 (m, 4H), 7.57 (br, 2H), 8.52 (d, 1H, J=4.9 Hz), 8.57 (d, 1H, J=4.9 Hz).
EXAMPLE 55 Synthesis of 4-[N-(indan-5-yl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine dihydrochloride
Figure US06867221-20050315-C00160
4-(5-Indanylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (60 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a dihydrochloride.
Yield: 18 mg (19%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.60-1.95 (m, 4H), 2.00 (quint, 2H, J=7.2 Hz), 2.20 (br, 2H), 2.75-2.81 (m, 4H), 2.95 (br, 2H), 3.60 (br, 2H), 3.85 (br, 1H), 3.86 (s, 3H), 3.87 (s, 6H), 3.88 (s, 3H), 3.94 (s, 6H), 4.51 (s, 2H), 6.54 (d, 1H, J=8.2 Hz), 6.66 (s, 1H), 6.70 (s, 2H), 7.01 (d, 1H, J=8.4 Hz), 7.19 (d, 1H, J=4.9 Hz), 7.19-7.42 (m, 6H), 7.60 (br, 1H), 8.59 (br, 1H).
EXAMPLE 56 Synthesis of 4-[N-(indan-5-yl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00161
4-(5-Indanylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (143 mg) and 5-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a trihydrochloride.
Yield: 138 mg (63%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.71-1.91 (m, 4H), 1.98-2.06 (m, 2H), 2.13-2.22 (m, 2H), 2.76-2.84 (m, 4H), 2.94-3.05 (m, 2H), 3.57 (s, 2H), 3.69-3.78 (m, 1H), 3.89 (s, 3H), 3.90 (s, 3H), 3.94 (s, 6H), 3.96 (s, 6H), 4.50 (s, 2H), 6.57 (dd, 1H, J=8.2 Hz, 2.3 Hz), 6.67 (s, 1H), 7.04 (d, 1H, J=8.4 Hz), 7.20-7.22 (m, 1H), 7.22 (s, 2H), 7.23 (s, 2H), 7.57-7.62 (m, 1H), 7.60 (s, 1H), 7.65 (dd, 1H, J=8.2 Hz, 2.2 Hz), 8.58-8.62 (m, 2H).
EXAMPLE 57 Synthesis of 4-[N-(indan-5-yl)-N-[4-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine dihydrochloride
Figure US06867221-20050315-C00162
4-(5-Indanylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (143 mg) and 4-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a dihydrochloride.
Yield: 95 mg (39%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.74-1.90 (m, 4H), 2.01-2.06 (m, 2H), 2.16-2.22 (m, 2H), 2.78-2.84 (m, 4H), 2.96-2.99 (m, 2H), 3.58 (s, 2H), 3.72 (br, 1H), 3.88 (s, 3H), 3.90 (s, 3H), 3.91 (s, 6H), 3.96 (s, 6H), 4.51 (s, 2H), 6.55 (d, 1H, J=8.3 Hz), 6.67 (s, 1H), 6.72 (s, 2H), 7.04 (d, 1H, J=8.3 Hz), 7.20 (d, 1H, J=5.1 Hz), 7.23 (s, 2H), 7.35 (d, 2H, J=8.1 Hz), 7.47 (d, 2H, J=8.1 Hz), 7.61 (s, 1H), 8.59 (d, 1H, J=4.9 Hz).
PREPARATION EXAMPLE 89 Synthesis of 4-(4-butylanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine
Figure US06867221-20050315-C00163
1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (1.24 g) and 4-butylaniline (149 mg) were reacted in the same manner as described in Preparation Example 37 to give the title compound.
Yield: 1.23 g (72%). 1H-NMR (400 MHz, CDCl3) δ: 0.82 (t, 3H, J=7.3 Hz), 1.20-1.30 (m, 2H), 1.38-1.50 (m, 4H), 1.92-2.25 (m, 4H), 2.40 (t, 2H, J=7.7 Hz), 2.77 (br, 2H), 3.21(br, 1H), 3.50 (s, 2H), 3.82 (s, 3H), 3.89 (s, 6H), 6.45 (d, 2H, J=7.8 Hz), 6.89 (d, 2H, J=8.0 Hz), 7.13 (d, 1H, J=4.9 Hz), 7.18 (s, 2H), 7.58 (s, 1H), 8.52 (d, 1H, J=4.9 Hz).
EXAMPLE 58 Synthesis of 4-[N-(4-butylphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-3-yl ]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00164
4-(4-Butylanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl ]methyl]piperidine (147 mg) and 3-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a trihydrochloride.
Yield: 58 mg (27%). 1NMR (400 MHz, measured as a free base, CDCl3) δ: 0.91 (t, 3H, J=7.3 Hz), 1.321.35 (m, 2H), 1.50-1.70 (m, 4H), 1.75 (br, 2H), 2.10-2.20 (m, 2H), 2.49 (t, 2H, J=7.6 Hz, 2.95 (br, 2H), 3.55 (s, 2H), 3.70 (br, 1H), 3.90 (s, 3H), 3.91 (s, 6H), 3.92 (s, 3H), 3.96 (s, 6H), 4.41 (s, 2H), 6.59 (d, 2H, J=8.8 Hz), 6.74 (s, 2H), 7.00 (d, 2H, J=8.6 Hz), 7.16-7.17 (m, 1H), 7.19 (d, 1H, J=4.9 Hz), 7.22 (s, 2H), 7.54 (s, 1H), 8.59 (d, 1H, J=7.5 Hz), 8.52 (br, 1H), 8.59 (d, 1H, J=4.9 Hz).
EXAMPLE 59 Synthesis of 4-[N-(4-butylphenyl)-N-[2-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine dihydrochloride
Figure US06867221-20050315-C00165
4-(4-Butylanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (147 mg) and 2-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a dihydrochloride.
Yield: 59 mg (24%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 0.90 (t, 3H, J=7.4 Hz), 1.251.41 (m, 2H),1.48-1.75 (m, 4H), 1.81 (d, 2H, J=11.7 Hz), 2.13 (t, 2H, J=11.2 Hz), 2.48 (t, 2H, J=7.5 Hz), 2.93 (d, 2H, J=11.2 Hz), 3.55 (s, 2H), 3.65-3.80 (m, 1H), 3.87 (s, 6H), 3.90 (s, 3H), 3.92 (s, 1H), 3.96 (s, 6H), 4.33 (s, 2H), 6.56 (s, 2H), 6.60 (d, 2H, J=8.5 Hz), 6.98 (d, 2H, J=8.5 Hz), 7.18 (d, 1H, J=4.9 Hz), 7.21 (s, 2H), 7.20-7.37 (m, 3H), 7.41 (br, 1H), 7.54 (s, 1H), 8.58 (d, 1H, J=4.9 Hz).
EXAMPLE 60 Synthesis of 4-[N-(4-buthylphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00166
4-(4-Butylanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (196 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (129 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as white powder after converting a free base to a trihydrochloride.
Yield: 20 mg (6%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 0.88 (t, 3H, J=1.3 Hz), 1.201.35 (m, 2H), 1.49-1.60 (m, 2H), 1.62-2.02 (m, 4H), 2.20 (br, 2H), 2.46 (t, 2H, J=7.3 Hz), 3.05 (br, 2H), 3.60 (br, 3H), 3.87 (s, 3H), 3.88 (s, 3H), 3.90 (s, 6H), 3.94 (s, 6H), 4.49 (s, 2H), 6.62 (d, 2H, J=8.3 Hz), 6.98 (d, 2H, J=8.3 Hz), 7.13 (s, 2H), 7.15-7.40 (m, 4H), 7.55 (br, 2H), 8.52 (d, 1H, J=4.9 Hz), 8.60 (br, 1H).
EXAMPLE 61 Synthesis of 4-[N-(4-butylphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine dihydrochloride
Figure US06867221-20050315-C00167
4-(4-Butylanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (147 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a dihydrochloride.
Yield: 102 mg (42%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 0.90 (t, 3H, J=7.4 Hz), 1.30-1.36 (m, 2H), 1.48-1.56 (m, 2H), 1.76-1.89 (m, 4H), 2.19 (br, 2H), 2.48 (t, 2H, J=7.8 Hz), 2.97 (br, 2H), 3.58 (s, 2H), 3.86 (br, 1H), 3.88 (s, 3H), 3.90 (s, 3H), 3.95 (s, 6H), 4.54 (s, 2H), 6.68 (d, 2H, J=8.6 Hz), 6.72 (s, 2H), 7.00 (d, 2H, J=8.6 Hz), 7.20-7.27 (m, 2H), 7.23 (s, 2H), 7.32-7.40 (m, 2H), 7.44 (s, 1H), 7.62 (s, 1H), 8.59 (d, 1H, J=5.1 Hz).
EXAMPLE 62 Synthesis of 4-[N-(4-butylphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00168
4-(4-Butylanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (147 mg) and 5-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a trihydrochloride.
Yield: 65 mg (21%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 0.90 (t, 3H, J=7.3 Hz), 1.321.36 (m, 2H), 1.50-1.54 (m, 2H), 1.70-1.95 (m, 4H), 2.17 (br, 2H), 2.49 (t, 2H, J=7.7 Hz), 2.96 (br, 2H), 3.58 (s, 2H), 3.75 (br, 1H), 3.89 (s, 3H), 3.90 (s, 3H), 3.94 (s, 6H), 3.96 (s, 6H), 4.50 (s, 2H), 6.68 (d, 2H, J=8.6 Hz), 7.00 (d, 2H, J=8.6 Hz), 7.20-7.22 (m, 3H), 7.23 (s, 2H), 7.58-7.66 (m, 3H), 8.59 (br, 1H), 8.60 (br, 1H).
EXAMPLE 63 Synthesis of 4-[N-(4-butylphenyl)-N-[4-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine dihydrochloride
Figure US06867221-20050315-C00169
4-(4-Butylanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (147 mg) and 4-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a dihydrochloride.
Yield: 82 mg (33%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 0.90 (t, 3H, J=7.3 Hz), 1.301.36 (m, 2H), 1.51-1.55 (m, 2H), 1.79-1.90 (m, 4H), 2.18 (br, 2H), 2.48 (t, 2H, J=7.7 Hz), 2.98 (d, 2H, J=10.7 Hz), 3.57 (s, 2H), 3.72-3.85 (m, 1H), 3.88 (s, 3H), 3.90 (s, 3H), 3.91 (s, 6H), 3.96 (s, 6H), 4.50 (s, 2H), 6.66 (d, 2H, J=8.8 Hz), 6.75 (s, 2H), 7.00 (d, 2H, J=8.8 Hz), 7.20 (d, 1H, J=4.9 Hz), 7.22 (s, 2H), 7.33 (d, 2H, J=8.2 Hz), 7.47 (d, 2H, J=8.2 Hz), 7.61 (s, 1H), 8.59 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 90 Synthesis of 1-(4-pycolyl)-4-piperidone
Figure US06867221-20050315-C00170
4-piperidone hydrochloride monohydrate (922 mg) and 4-picolyl chloride hydrochloride (820 mg) were reacted in the same manner as described in Example 9 to give the title compound.
Yield: 870 mg (92%). 1H-NMR (400 MHz, CDCl3) δ: 2.46 (t, 4H, J=5.9 Hz), 2.74 (t, 4H, J=6.2 Hz), 3.61 (s, 2H), 7.29 (d, 2H, J=6.2 Hz), 8.55 (dd, 2H, J=6.2 Hz, 1.1 Hz).
PREPARATION EXAMPLE 91 Synthesis of 1-(4-pycolyl)-4-(4-pycolylamino)piperidine tetrahydrochloride
Figure US06867221-20050315-C00171
1-(4-pycolyl)-4-piperidone (870 mg) and 4-picolylamine (497 mg) were coupled in the same manner as described in Preparation Example 37. The title compound was obtained as pale brown powder after converting a free base to tetrahydrochloride.
Yield: 363 mg (19%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.37-1.51 (m, 2H), 1.82-1.90 (m, 21T), 2.04 (dt, 2H, J=11.6 Hz, 2.7 Hz), 2.44-2.55 (m, 1H), 2.76-2.82 (m, 2H), 3.47 (s, 2H), 3.82 (s, 2H), 7.23-7.26 (m, 4H), 8.50-8.53 (m, 4H).
PREPARATION EXAMPLE 92 Synthesis of 4-(p-anisidino)-1-(tert-butoxycarbonyl)piperidine
Figure US06867221-20050315-C00172
1-(tert-Butoxycarbonyl)-4-piperidone (116 g) and p-anisidine (68.3 g) were condensed in the same manner as described in Preparation Example 37 to give the title compound.
Yield: 125 g (74%). 1H-NMR (400 MHz, CDCl3) δ: 1.23-1.35 (m, 2H), 1.46 (s, 9H), 1.96-2.06 (m, 2H), 2.83-2.96 (m, 2H), 3.27-3.38 (m, 1H), 3.74 (s, 9H), 3.94-4.12 (m, 2H), 6.58 (d, 2H, J=9.0 Hz), 6.77 (d, 2H, J=9.0 Hz).
PREPARATION EXAMPLE 93 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzoyl]amino]piperidine
Figure US06867221-20050315-C00173
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 3-(3,4,5-trimethoxyphenyl)benzoic acid (577 mg) were condensed in the same manner as described in Example 1 to give the title compound.
Yield: 416 mg (36%).
PREPARATION EXAMPLE 94 Synthesis of 4-[N-(4-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzoyl]amino]piperidine hydrochloride
Figure US06867221-20050315-C00174
To a solution of 1-(tert-butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzoyl]amino]piperidine (416 mg) in ethyl acetate (5 mL) was added 4 M hydrogen chloride in ethyl acetate (5 mL). The mixture was stirred at room temperature for 4 hr, resulting precipitates were collected and washed with ethyl acetate on a funnel to give the title compound.
Yield: 315 mg (85%)
EXAMPLES 64 TO 66
These compounds were prepared by the condensation of 4-[N-(4-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzoyl]amino]piperidine hydrochloride with chloride derivatives obtained in Preparation Examples 3, 42 and 48. Free bases obtained were then converted to the corresponding hydrochlorides.
Yields and NMR data of their free bases are listed below.
Ex-
am- NMR data (400 MHz, measured
ple Structure Yield as free bases, CDCl3) δ
64
Figure US06867221-20050315-C00175
 		68% 1.53-1.55(m, 2H), 1.89(d, 2H, J=12.0Hz), 2.23(t, 2H, J=12.0 Hz), 2.91(d, 2H, J=11.0Hz), 3.51 (s, 2H), 3.70(s, 3H), 3.84(s, 3H), 3.87(s, 9H), 3.92(s, 6H), 4.78(br, 1H), 6.54(s, 2H), 6.72(d, 2H, J=8.5Hz), 6.94(d, 2H, J=8.5Hz), 7.13-7.20(m, 4H), 7.18(s, 2H),
# 7.32(d, 1H, J=5.3Hz), 7.45(s, 1H), 8.19(d, 1H, J=4.9Hz).
65
Figure US06867221-20050315-C00176
 		52% 1.66-1.89(m, 4H), 2.05-2.17(m, 2H), 2.97(d, 2H, J=10.3Hz), 3.43-3.60(m, 1H), 3.57(s, 2H), 3.86(s, 3H), 3.87(s, 6H), 3.91(s, 6H), 4.42(s, 2H), 6.63(s, 2H), 6.72-6.79(m, 6H), 7.64(s, 1H), 7.78(br, 1H), 8.46(d, 2H, J=1.6 Hz), 8.59(d, 1H, J=2.4Hz), 8.68
# (d, 1H, J=2.2Hz).
66
Figure US06867221-20050315-C00177
 		75% 1.42-1.58(m, 2H), 1.85-1.92(m, 2H), 2.14-2.23(m, 2H), 2.93-3.03 (m, 2H), 3.56(s, 2H), 3.70(s, 3H), (m, 2H), 3.56(s, 2H), 3.70(s, 3H), 3.85(s, 3H), 3.87(s, 3H), 3.87(s, 6H), 3.90(s, 6H), 4.79(br, 1H), 6.54(s, 2H), 6.70(d, 2H, J=8.9 Hz), 6.74(s, 2H), 6.93(d, 2H,
# J=8.9Hz), 7.17-7.23(m, 3H), 7.31-7.43(m, 5H).
PREPARATION EXAMPLE 95 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00178
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (2.21 g) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (2.12 g) were condensed in the same manner as described in Example 9 to give the title compound.
Yield: 3.76 g (93%). 1H-NMR (400 MHz, CDCl3) δ: 1.40-1.64 (m, 2H), 1.44 (s, 9H), 1.82-1.91 (m, 2H), 2.71-2.84 (m, 2H), 3.62-3.73 (m, 1H), 3.74 (s, 3H), 3.89 (s, 3H), 3.94 (s, 6H), 4.10-4.30 (m, 2H), 4.40 (s, 2H), 6.76 (d, 2H, J=9.4 Hz), 6.79 (d, 2H, J=9.8 Hz), 7.14-7.19 (m, 3H), 7.56 (s, 1H), 8.55 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 96 Synthesis of 4-[N-(4-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00179
1-(tert-Butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine (3.76 g) was treated in the same manner as described in Preparation Example 94 to give the title compound.
Yield: 3.77 g (theoretical yield).
PREPARATION EXAMPLE 97 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00180
4-(p-anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Preparation Example 9 to give pale yellow amorphous of the title compound.
Yield: 159 mg (14%). 1H-NMR (400 MHz, CDCl3) δ: 1.44 (s, 9H), 1.50-1.65 (m, 2H), 1.83-1.91 (m, 2H), 2.70-2.84 (m, 2H), 3.53-3.62 (m, 1H), 3.73 (s, 3H), 3.89 (s, 3H), 3.91 (s, 6H), 4.10-4.29 (m, 2H), 4.41 (s, 2H), 6.66 (s, 2H), 6.76-6.84 (m, 4H), 7.70 (s, 1H), 8.49 (s, 1H), 8.63 (d, 1H, J=2.1 Hz).
PREPARATION EXAMPLE 98 Synthesis of 4-[N-(4-methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00181
1-(tert-Butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine (159 mg) was treated in the same manner as described in Preparation Example 94 to give pale yellow powder of the title compound.
Yield: 142 mg (94%).
PREPARATION EXAMPLE 99 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine
Figure US06867221-20050315-C00182
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give pale yellow amorphous of the title compound.
Yield: 1.12 g (90%). 1H-NMR (400 MHz, CDCl3) δ: 1.44 (s, 9H), 1.50-1.63 (m, 2H), 1.82-1.91 (m, 2H), 2.71-2.83 (m, 2H), 3.69 (tt, 1H, J=11.5 Hz, 3.5 Hz), 3.73 (s, 3H), 3.88 (s, 3H), 3.90 (s, 6H), 4.10-4.28 (m, 2H), 4.42 (s, 2H), 6.71 (s, 2H), 6.78 (s, 4H), 7.24-7.28 (m, 1H), 7.31-7.40 (m, 2H), 7.42 (s, 1H).
PREPARATION EXAMPLE 100 Synthesis of 4-[N-(4-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine hydrochloride
Figure US06867221-20050315-C00183
1-(tert-Butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (1.12 g) was treated in the same manner as described in Preparation Example 94 to give pale yellow powder of the title compound.
Yield: 980 mg (99%).
EXAMPLES 67 TO 71
These compounds were obtained by the condensation of amines obtained in Preparation Examples 96, 98 and 100 with chloride derivatives obtained in Preparation Examples 42 and 48. Free bases obtained were then converted to the corresponding hydrochlorides. Yields and NMR data of their free bases are listed below.
Ex-
am- NMR data (400 MHz, measured
ple Structure Yield as free bases, CDCl3) δ
67
Figure US06867221-20050315-C00184
 		62% 1.60-1.92(m, 4H), 2.08-2.22(m, 2H), 2.92-3.06(m, 2H), 3.54-3.64 (m, 3H), 3.73(s, 3H), 3.89(s, 3H), 3.90(s, 3H), 3.93(s, 12H), 4.43(s, 2H), 6.70-6.81(m, 6H), 7.12-7.17(m, 3H), 7.56(s, 1H), 7.76(s, 1H), 8.49(d, 1H, J=1.8 Hz), 8.53(d, 1H, J=5.1Hz), 8.70
# (s, 1H).
68
Figure US06867221-20050315-C00185
 		54% 1.65-1.79(m, 2H), 1.81-1.90(m, 2H), 2.04-2.18(m, 2H), 2.94-3.06 (m, 2H), 3.52-3.66(m, 3H), 3.72 (s, 3H), 3.89(s, 6H), 3.92(s, 6H), 3.93(s, 6H), 4.44(s, 2H), 6.70- 6.80(m, 6H), 7.13-7.17(m, 3H), 7.24-7.50(m, 4H), 7.55(s, 1H), 8.53(d, 1H, J=4.9Hz).
69
Figure US06867221-20050315-C00186
 		52% 1.66-1.89(m, 4H), 2.05-2.17(m, 2H), 2.97(d, 2H, J=10.3Hz), 3.43-3.60(m, 1H), 3.57(s, 2H), 3.86(s, 3H), 3.87(s, 6H), 3.91(s, 6H), 4.42(s, 2H), 6.63(s, 2H), 6.72-6.79(m, 6H), 7.64(s, 1H), 7.78(br, 1H), 8.46(d, 2H, J=1.6 Hz), 8.59(d, 1H, J=2.4Hz), 8.68
# (d, 1H, J=2.2Hz).
70
Figure US06867221-20050315-C00187
 		69% 1.55-1.97(m, 4H), 2.06-2.21(m, 2H), 2.92-3.07(m, 2H), 3.53-3.68 (m, 3H), 3.72(s, 3H), 3.87(s, 3H), 3.89(s, 6H), 3.94(s, 3H), 4.46(s, 2H), 6.69(s, 2H), 6.73- 6.82(m, 6H), 7.22-7.29(m, 1H), 7.32(t, 1H, J=7.4Hz), 7.36(d, 1H, J=7.8Hz), 7.41(s, 1H),
# 7.79(br, 1H), 8.48(s, 1H), 8.71(br, 1H).
71
Figure US06867221-20050315-C00188
 		75% 1.69-1.89(m, 4H), 2.06-2.15(m, 2H), 2.96-3.04(m, 2H), 3.56-3.66 (m, 1H), 3.57(s, 2H), 3.72(s, 3H), 3.87(s, 3H), 3.89(s, 9H), 3.92(s, 6H), 4.46(s, 2H), 6.70(s, 2H), 6.71-6.79(m, 6H), 7.23-7.47 (m, 8H).
PREPARATION EXAMPLE 101 Synthesis of 1-(tert-butoxycarbonyl)-4-(4-ethoxyphenylamino)piperidine
Figure US06867221-20050315-C00189
1-(tert-butoxycarbonyl)-4-piperidinone (5.00 g) and p-phenetidine (3.28 g) was treated in the same manner as described in Preparation Example 37 to give brown powder of the title compound.
Yield: 7.00 g (91%). 1H-NMR (400 MHz, CDCl3) δ: 1.21-1.31 (m, 2H), 1.37 (t, 3H, J=7.0 Hz), 1.46 (s, 9H), 1.97-2.05 (m, 2H), 2.84-2.95 (m, 2H), 3.28-3.37 (m, 1H), 3.96 (q, 2H, J=7.0 Hz), 3.99-4.10 (m, 2H), 6.57 (d, 2H, J=8.8 Hz), 6.77 (d, 2H, J=9.0 Hz).
PREPARATION EXAMPLE 102 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-ethoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00190
1-(tert-Butoxycarbonyl)-4-[(4-ethoxyphenyl)amino]piperidine (641 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 1.08 g (94%). 1H-NMR (400 MHz, CDCl3) δ: 1.36 (t, 3H, J=7.9 Hz), 1.44 (s, 9H), 1.49-1.58 (m, 2H), 1.82-1.92 (m, 2H), 2.70-2.85 (m, 2H), 3.62-3.72 (m, 1H), 3.89 (s, 3H), 3.94 (s, 6H), 4.12-4.29 (m, 2H), 4.39 (s, 2H), 6.75 (d, 2H, J=9.2 Hz), 6.78 (d, 2H, J=9.6 Hz), 7.14-7.18 (m, 3H), 7.55 (s, 1H), 8.54 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 103 Synthesis of 4-[N-(4-ethoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00191
1-(tert-Butoxycarbonyl)-4-[N-(4-ethoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine (1.08 g) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 1.01 g (98%).
PREPARATION EXAMPLE 104 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-ethoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00192
1-(tert-Butoxycarbonyl)-4-[(4-ethoxyphenyl)amino]piperidine (641 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 452 mg (39%). 1H-NMR (400 MHz, CDCl3) δ: 1.36 (t, 3H, J=6.8 Hz), 1.44 (s, 9H), 1.50-1.60 (m, 2H), 1.82-1.90 (m, 1H), 2.68-2.82 (m, 2H), 3.52-3.61 (m, 1H), 3.88 (s, 3H), 3.90 (s, 6H), 3.94 (q, 2H, J=7.0 Hz), 4.10-4.25 (m, 2H), 4.40 (s, 2H), 6.66 (s, 2H), 6.77 (d, 2H, J=9.2 Hz), 6.81 (d, 2H, J=9.2 Hz), 7.67 (s, 1H), 8.49 (d, 1H, J=2.0 Hz), 8.62 (d, 1H, J=2.1 Hz).
PREPARATION EXAMPLE 105 Synthesis of 4-[N-(4-ethoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00193
1-(tert-Butoxycarbonyl)-4-[N-(4-ethoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine (452 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 380 mg (88%).
PREPARATION EXAMPLE 106 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-ethoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine
Figure US06867221-20050315-C00194
1-(tert-Butoxycarbonyl)-4-[(4-ethoxyphenyl)amino]piperidine (641 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 1.06 g (92%). 1H-NMR (400 MHz, CDCl3) δ: 1.36 (t, 3H, J=7.0 Hz), 1.44 (s, 9H), 1.53-1.59 (m, 2H), 1.83-1.91 (m, 2H), 2.70-2.83 (m, 2H), 3.64-3.73 (m, 1H), 3.88 (s, 3H), 3.90 (s, 6H), 3.94 (q, 2H, J=7.0 Hz), 4.10-4.29 (m, 2H), 4.41 (s, 2H), 6.71 (s, 2H), 6.76 (s, 4H), 7.26 (d, 1H, J=7.9 Hz), 7.33 (dd, 1H, J=7.4 Hz, 7.4 Hz), 7.38 (d, 1H, J=7.6 Hz), 7.42 (s, 1H),
PREPARATION EXAMPLE 107 Synthesis of 4-[N-(4-ethoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine hydrochloride
Figure US06867221-20050315-C00195
1-(tert-Butoxycarbonyl)-4-[N-(4-ethoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (1.06 g) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 913 mg (97%).
EXAMPLES 72 TO 79
These compounds were obtained by the condensation of amines obtained in Preparation Examples 103, 105 and 107 with chloride derivatives obtained in Preparation Examples 3, 42 and 48. Free bases obtained were then converted to the corresponding hydrochlorides. Yields and NMR data of their free bases are listed below.
Ex-
am- NMR data (400 MHz, measured as
ple Structure Yield free bases, CDCl3) δ
72
Figure US06867221-20050315-C00196
 		49% 1.36(t, 3H, J=7.1Hz), 1.68-1.94 (m, 4H), 2.10-2.24(m, 2H), 2.93- 3.04(m, 2H), 3.54-3.65(m, 3H), 3.89(s, 3H), 3.90(s, 3H), 3.93(s, 6H), 3.96(s, 6H), 4.45(s, 2H), 6.72(d, 2H, J=9.2Hz), 6.78(d, 2H, J=9.3Hz), 7.15(s, 2H), 7.17 (d, 1H, J=6.1Hz), 7.20(dd, 1H,
# J=4.9Hz, 1.0Hz), 7.23(s, 2H), 7.57(s, 1H), 7.61(br, 1H), 8.54(d, 1H, J=5.2Hz), 8.59(d, 1H, J=4.9 Hz).
73
Figure US06867221-20050315-C00197
 		63% 1.36(t, 3H, J=7.0Hz), 1.56-1.74 (m, 2H), 1.80-1.90(m, 2H), 2.07- 2.19(m, 2H), 2.92-3.02(m, 2H), 3.58(s, 2H), 3.88-3.95(m, 2H), 3.89(s, 3H), 3.93(s, 12H), 4.43 (s, 2H), 6.69-6.79(m, 6H), 7.12- 7.17(m, 3H), 7.55(s, 1H), 7.76(s, 1H), 8.49(d, 1H, J=1.8Hz), 8.53
# (d, 1H, J=5.1Hz), 8.69(s, 1H).
74
Figure US06867221-20050315-C00198
 		65% 1.36(t, 3H, J=7.0Hz), 1.58-1.78 (m, 2H), 1.80-1.89(m, 2H), 2.04- 2.16(m, 2H), 2.95-3.05(m, 2H), 3.52-3.66(m, 1H), 3.57(s, 1H), 3.85-3.97(m, 2H), 3.89(s, 6H), 3.92(s, 6H), 3.93(s, 6H), 4.44(s, 2H), 6.67-6.80(m, 6H), 7.13-7.18 (m, 3H), 7.25-7.31(m, 1H), 7.37
# (dd, 1H, J=7.6Hz, 7.6Hz), 7.41- 7.48(m, 2H), 7.55(s, 1H), 8.53 (d, 1H, J=4.9Hz).
75
Figure US06867221-20050315-C00199
 		42% 1.36(t, 3H, J=7.0Hz), 1.74-2.34 (m, 6H), 2.96-3.10(m, 2H), 3.47- 3.73(m, 3H), 3.87-3.98(m, 2H), 3.88(s, 3H), 3.90(s, 9H), 3.97(s, 6H), 4.44(s, 2H), 6.65(s, 2H), 6.74-6.82(m, 4H), 7.18-7.32(m, 4H), 7.67(s, 1H), 8.49(d, 1H, J=1.6Hz), 8.57-8.65(m, 2H).
76
Figure US06867221-20050315-C00200
 		43% 1.36(t, 3H, J=6.8Hz), 1.63-1.96 (m, 4H), 2.00-2.26(m, 2H), 2.92- 3.03(m, 2H), 3.44-3.66(m, 3H), 3.86-3.96(m, 2H), 3.88(s, 3H), 3.89(s, 6H), 3.90(s, 3H), 3.93(s, 6H), 4.44(s, 2H), 6.65(s, 2H), 6.72-6.80(m, 6H), 7.67(s, 1H), 7.77(br, 1H), 8.47-8.53(m, 2H),
# 8.62(d, 1H, J=1.9Hz), 8.70(s, 1H).
77
Figure US06867221-20050315-C00201
 		82% 1.35(t, 3H, J=6.8Hz), 1.70-1.82 (m, 2H), 1.84-1.92(m, 2H), 2.10- 2.19(m, 2H), 2.92-3.00(m, 2H), 3.52-3.65(m, 3H), 3.88(s, 3H), 3.89(s, 6H), 3.90(s, 3H), 3.93(q, 2H, J=7.1Hz), 3.96(s, 6H), 4.47 (s, 2H), 6.70(s, 2H), 6.73(d, 2H, J=9.3Hz), 6.77(d, 2H, J=9.3Hz),
# 7.18-7.28(m, 4H), 7.33(dd, 1H, J=7.3Hz, 7.3Hz), 7.37(d, 1H, J=7.6Hz), 7.43(s, 1H), 7.59(s, 1H), 8.58(d, 1H, J=4.9Hz).
78
Figure US06867221-20050315-C00202
 		61% 1.35(t, 3H, J=6.9Hz), 1.58-1.80 (m, 2H), 1.82-1.91(m, 2H), 2.09- 2.18(m, 2H), 2.93-3.20(m, 2H), 3.56-3.65(m, 1H), 3.58(s, 2H), 3.87(s, 3H), 3.89(s, 6H), 3.89(s, 3H), 3.91-3.94(m, 2H), 3.93(s, 6H), 4.45(s, 2H), 6.69(s, 2H), 6.71-6.78(m, 6H), 7.23-7.28(m,
# 1H), 7.32(t, 1H, J=7.5Hz), 7.36 (d, 1H, J=7.6Hz), 7.42(s, 1H), 7.77(s, 1H), 8.49(d, 1H, J=1.8 Hz), 8.69(d, 1H, J=1.8Hz).
79
Figure US06867221-20050315-C00203
 		73% 1.35(t, 3H, J=6.8Hz), 1.68-1.80 (m, 2H), 1.81-1.89(m, 2H), 2.06- 2.14(m, 2H), 2.96-3.03(m, 2H), 3.57(s, 2H), 3.57-3.65(m, 1H), 3.87(s, 3H), 3.89(s, 9H), 3.91- 3.96(m, 2H), 3.92(s, 6H), 4.46(s, 2H), 6.69-6.79(m, 9H), 7.23-7.47 (m, 7H).
PREPARATION EXAMPLE 108 Synthesis of 1-(tert-butoxycarbonyl)-4-(4-butoxyphenylamino)piperidine
Figure US06867221-20050315-C00204
1-(tert-butoxycarbonyl)-4-piperidone (5.00 g) and 4-butoxyaniline (3.95 g) was treated in the same manner as described in Preparation Example 37 to give brown powder of the title compound.
Yield: 6.91 g (83%). 1H-NMR (400 MHz, CDCl3) δ: 0.96 (t, 3H, J=7.2 Hz), 1.23-1.35 (m, 2H), 1.42-1.53 (m, 2H), 1.46 (s, 9H), 1.68-1.76 (m, 2H), 1.97-2.05 (m, 2H), 2.84-2.95 (m, 2H), 3.28-3.37 (m, 1H), 3.88 (t, 2H, J=6.6 Hz), 3.96-4.12 (m, 2H), 6.57 (d, 2H, J=9.0 Hz), 6.77 (d, 2H, J=8.8 Hz).
PREPARATION EXAMPLE 109 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-butoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00205
1-(tert-Butoxycarbonyl)-4-[(4-butoxyphenyl)amino]piperidine (696 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 980 mg (81%). 1H-NMR (400 MHz, CDCl3) δ: 0.95 (t, 3H, J=7.4 Hz), 1.40-1.50 (m, 2H), 1.44 (s, 9H), 1.67-1.76 (m, 2H), 1.82-1.90 (m, 2H), 1.82-1.90 (m, 2H), 2.70-2.82 (m, 2H), 3.61-3.71 (m, 1H), 3.84-3.90 (m, 5H), 3.94 (s, 6H), 4.10-4.28 (m, 2H), 4.39 (s, 2H), 6.74 (d, 2H, J=9.4 Hz), 6.78 (d, 2H, J=9.4 Hz), 7.14-7.18 (m, 3H), 7.56 (s, 1H), 8.54 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 110 Synthesis of 4-[N-(4-butoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00206
1-(tert-Butoxycarbonyl)-4-[N-(4-butoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine (980 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 926 mg (99%).
PREPARATION EXAMPLE 111 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-butoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00207
1-(tert-Butoxycarbonyl)-4-[(4-butoxyphenyl)amino]piperidine (697 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 485 mg (40%). 1H-NMR (400 MHz, CDCl3) δ: 0.95 (t, 3H, J=7.4 Hz), 1.40-1.57 (m, 2H), 1.44 (s, 9H), 1.67-1.75 (m, 2H), 1.82-1.90 (m, 2H), 2.69-2.81 (m, 2H), 3.51-3.60 (m, 1H), 3.87 (q, 2H, J=6.6 Hz), 3.88 (s, 3H), 3.90 (s, 6H), 4.06-4.23 (m, 2H), 4.39 (s, 2H), 6.66 (s, 2H), 6.77 (d, 2H, J=9.2 Hz), 6.81 (d, 2H, J=9.2 Hz), 6.81 (d, 2H, J=9.4 Hz), 7.67 (s, 1H), 8.49 (d, 1H, J=1.8 Hz), 8.62 (d, 1H, J=2.2 Hz).
PREPARATION EXAMPLE 112 Synthesis of 4-[N-(4-butoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00208
1-(tert-Butoxycarbonyl)-4-[N-(4-butoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine (485 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 456 mg (98%).
PREPARATION EXAMPLE 113 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-butoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine
Figure US06867221-20050315-C00209
1-(tert-Butoxycarbonyl)-4-[(4-butoxyphenyl)amino]piperidine (697 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 1.17 g (97%). 1H-NMR (400 MHz, CDCl3) δ: 0.95 (t, 3H, J=7.3 Hz), 1.40-1.61 (m, 4H), 1.44 (s, 9H), 1.67-1.75 (m, 2H), 1.83-1.90 (m, 2H), 2.70-2.83 (m, 2H), 3.63-3.72 (m, 2H), 3.87 (q, 2H, J=6.6 Hz), 3.88 (s, 3H), 3.90 (s, 6H), 4.09-4.28 (m, 2H), 4.41 (s, 2H), 6.70 (s, 2H), 6.76 (s, 4H), 7.26 (d, 2H, J=8.0 Hz), 7.33 (t, 1H, J=7.6 Hz), 7.38 (d, 1H, J=7.3 Hz), 7.42 (s, 1H).
PREPARATION EXAMPLE 114 Synthesis of 4-[N-(4-butoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine hydrochloride
Figure US06867221-20050315-C00210
1-(tert-Butoxycarbonyl)-4-[N-(4-butoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (1.17 g) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 1.02 g (98%).
EXAMPLES 80 TO 87
These compounds were obtained by the condensation of amines obtained in Preparation Examples 110, 112 and 114 with chloride derivatives obtained in Preparation Examples 3, 42 and 48. Free bases obtained were then converted to the corresponding hydrochlorides. Yields and NMR data of their free bases are listed below.
Ex-
am- NMR data (400 MHz, measured as
ple Structure Yield free bases, CDCl3) δ
80
Figure US06867221-20050315-C00211
 		63% 0.95(t, 3H, J=7.3Hz), 1.40-1.51 (m, 2H), 1.66-1.79(m, 2H), 1.83- 1.92(m, 2H), 2.10-2.21(m, 2H), 2.92-3.02(m, 2H), 3.53-3.63(m, 3H), 3.84-3.90(m, 2H), 3.89(s, 3H), 3.93(s, 6H), 3.96(s, 6H), 6.72(d, 2H, J=9.3Hz), 6.77(d, 2H, J=9.3Hz), 7.15(s, 2H), 7.17
# (d, 1H, J=5.1Hz), 7.20(d, 1H, J=6.1Hz), 7.22(s, 2H), 7.57(s, 1H), 7.59(s, 1H), 8.54(d, 1H, J=4.9Hz), 8.59(d, 1H, J=5.1Hz).
81
Figure US06867221-20050315-C00212
 		44% 0.95(t, 3H, J=7.4Hz), 1.42-1.51 (m, 2H), 1.67-1.76(m, 4H), 1.80- 1.91(m, 2H), 2.08-2.20(m, 2H), 2.92-3.03(m, 2H), 3.84-3.96(m, 3H), 3.89(s, 3H), 3.90(s, 3H), 3.93(s, 12H), 4.43(s, 2H), 6.69- 6.79(m, 6H), 7.14(s, 2H), 7.16 (d, 1H, J=5.2Hz), 7.55(s, 1H),
# 7.76(s, 1H), 8.49(d, 1H, J=1.8 Hz), 8.53(d, 1H, J=5.0Hz), 8.69 (s, 1H).
82
Figure US06867221-20050315-C00213
 		53% 0.95(t, 3H, J=7.2Hz), 1.40-1.51 (m, 2H), 1.65-1.78(m, 4H), 1.81- (m, 2H), 2.05-2.18(m, 2H), 1.89(m, 2H), 2.05-2.18(m, 2H), 3.05-3.06(m, 2H), 3.54-3.65(m, 3H), 3.84-3.96(m, 20H), 4.44(s, 2H), 6.70(d, 2H, J=9.2Hz), 6.74- 6.80(m, 4H), 7.11-7.19(m, 3H),
# 7.22-7.32(m, 1H), 7.34-7.50(m, 3H), 7.55(s, 1H), 8.53(d, 1H, J=5.1Hz).
83
Figure US06867221-20050315-C00214
 		42% 0.95(t, 3H, 7.4Hz), 1.40-1.5 1(m, 2H), 1.67-1.86(m, 6H), 2.03-2.30 (m, 2H), 2.92-3.06(m, 2H), 3.46- 3.56(m, 1H), 3.60(s, 2H), 3.84- 3.91(m, 2H), 3.88(s, 3H), 3.89(s, 6H), 3.90(s, 3H), 3.96(s, 6H), 4.44(s, 2H), 6.65(s, 2H), 6.74- 6.81(m, 4H), 7.20(d, 1H, J=4.9
# Hz), 7.25(s, 2H), 7.67(br, 2H), 8.50(d, 1H, J=1.6Hz), 8.60(d, 1H, J=5.6Hz).
84
Figure US06867221-20050315-C00215
 		36% 0.95(t, 3H, J=7.4Hz), 1.40-1.51 (m, 2H), 1.66-1.79(m, 4H), 1.82- 1.92(m, 2H), 2.00-2.22(m, 2H), 2.83-3.06(m, 2H), 3.44-3.67(m, 3H), 3.82-3.97(m, 2H), 3.88(s, 3H), 3.89(s, 6H), 3.90(s, 3H), 3.93(s, 6H), 4.44(s, 2H), 6.65(s, 2H), 6.72-6.80(m, 6H), 7.67(s,
# 1H), 7.76(br, 1H), 8.47-8.53(m, 2H), 8.62(d, 1H, J=2.2Hz), 8.70 (s, 1H).
85
Figure US06867221-20050315-C00216
 		72% 0.95(t, 3H, J=7.3Hz), 1.40-1.51 (m, 2H), 1.66-1.82(m, 4H), 1.84- (m, 2H), 2.10-2.20(m, 2H), 1.92(m, 2H), 2.10-2.20(m, 2H), 2.92-3.00(m, 2H), 3.53-3.66(m, 3H), 3.83-3.92(m, 2H), 3.88(s, 3H), 3.89(s, 6H), 3.90(s, 3H), 3.96(s, 6H), 4.47(s, 2H), 6.67(s,
# 2H), 6.73(d, 2H, J=9.2Hz), 6.77 (d, 2H, J=9.5Hz), 7.18-7.29(m, 4H), 7.33(dd, 1H, J=7.3Hz, 7.3 Hz), 7.37(d, 1H, J=7.6Hz), 7.43 (s, 1H), 7.60(s, 1H), 8.58(d, 1H, J=4.9Hz).
86
Figure US06867221-20050315-C00217
 		24% 0.94(t, 3H,J=7.4Hz), 1.41-1.51 (m, 2H), 1.61-1.80(m, 4H), 1.82- 1.92(m, 2H), 2.08-2.19(m, 2H), 2.92-3.02(m, 2H), 3.55-3.65(m, 1H), 3.57(s, 2H), 3.84-3.91(m, 2H), 3.87(s, 3H), 3.88(s, 6H), 3.89(s, 3H), 3.93(s, 6H), 4.45(s, 2H), 6.69(s, 2H), 6.71-6.78(m,
# 4H), 6.75(s, 2H), 7.23-7.28(m, 1H), 7.32(t, 1H, J=7.4Hz), 7.36 (d, 1H, J=7.6Hz), 7.42(s, 1H), 7.77(s, 1H), 8.49(d, 1H, J=1.6 Hz), 8.69(s, 1H).
87
Figure US06867221-20050315-C00218
 		78% 0.94(t, 3H, J=7.3Hz), 1.40-1.50 (m, 2H), 1.66-1.88(m, 4H), 1.82- 1.89(m, 2H), 2.04-2.16(m, 2H), 2.96-3.03(m, 2H), 3.55-3.65(m, 3H), 3.83-3.90(m, 2H), 3.87(s, 3H), 3.89(s, 9H), 3.92(s, 6H), 4.46(s, 2H), 6.69-6.79(m, 9H), 7.23-7.48(m, 7H).
PREPARATION EXAMPLE 115 Synthesis of 4-(m-anisidino)-1-(tert-butoxycarbonyl)piperidine
Figure US06867221-20050315-C00219
1-(tert-Butoxycarbonyl)-4-piperidone (4.78 g) and m-anisidine (2.96 g) were condensed in the same manner as described in Preparation Example 37 to give the title compound.
Yield: 4.83 g (66%). 1H-NMR (400 MHz, CDCl3) δ: 1.20-1.39 (m, 2H), 1.44 (s, 9H), 1.99-2.05 (m, 2H), 2.89 (dt, 2H, J=13.5 Hz, 2.2 Hz), 3.33-3.44 (m, 1H), 3.75 (s, 3H), 3.96-4.07 (m, 2H), 6.14 (t, 1H, J=2.2 Hz), 6.18-6.29 (m, 2H), 7.05 (t, 1H, J=8.1 Hz).
PREPARATION EXAMPLE 116 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(3-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00220
4-(m-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 789 mg (70%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.50-1.67 (m, 2H), 1.82-1.91 (m, 2H), 2.74-2.87 (m, 2H), 3.74 (s, 3H), 3.88-3.98 (m, 1H), 3.89 (s, 3H), 3.94 (s, 6H), 4.14-4.32 (m, 2H), 4.48 (s, 2H), 6.28 (dd, 1H, J=2.2 Hz, 2.2 Hz), 6.31-6.37 (m, 2H), 7.10-7.15 (m, 2H), 7.16 (s, 2H), 7.55 (s, 1H), 8.56 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 117 Synthesis of 4-[N-(3-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00221
1-(tert-Butoxycarbonyl)-4-[N-(3-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine (789 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 710 mg (95%).
PREPARATION EXAMPLE 118 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(3-methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00222
4-(m-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 396 mg (35%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.54-1.66 (m, 2H), 1.81-1.91 (m, 2H), 2.73-2.87 (m, 2H), 3.74 (s, 3H), 3.87-3.93 (m, 1H), 3.88 (s, 3H), 3.90 (s, 6H), 4.14-4.29 (m, 2H), 4.51 (s, 2H), 6.30-6.35 (m, 2H), 6.38 (d, 1H, J=7.2 Hz), 6.68 (s, 2H), 7.12 (dd, 1H, J=8.8 Hz, 8.8 Hz), 7.66 (s, 1H), 8.49 (d, 1H, J=2.0 Hz), 8.66 (d, 1H, J=2.2 Hz).
PREPARATION EXAMPLE 119 Synthesis of 4-[N-(3-methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00223
1-(tert-Butoxycarbonyl)-4-[N-(3-methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine (396 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 348 mg (92%).
PREPARATION EXAMPLE 120 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(3-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine
Figure US06867221-20050315-C00224
4-(m-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Preparation Example 9 to give light yellow amorphous of the title compound.
Yield: 1.01 g (90%). 1H-NMR (400 MHz, CDCl3) δ: 1.44 (s, 9H), 1.56-1.67 (m, 2H), 1.83-1.91 (m, 2H), 2.72-2.86 (m, 2H), 3.73 (s, 3H), 3.85-3.98 (m, 1H), 3.88 (s, 3H), 3.90 (s, 6H), 4.12-4.30 (m, 2H), 4.50 (s, 2H), 6.27-6.34 (m, 2H), 6.38 (dd, 1H, J=8.2 Hz, 2.4 Hz), 6.72 (s, 2H), 7.10 (dd, 1H, J=8.2 Hz, 8.2 Hz), 7.21-7.27 (m, 1H), 7.32-7.43 (m, 3H).
PREPARATION EXAMPLE 121 Synthesis of 4-[N-(3-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine hydrochloride
Figure US06867221-20050315-C00225
1-(tert-Butoxycarbonyl)-4-[N-(3-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (1.01 g) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 820 mg (92%).
EXAMPLES 88 TO 95
These compounds were obtained by the condensation of amines obtained in Preparation Examples 117, 119 and 121 with chloride derivatives obtained in Preparation Examples 3, 42 and 48. Free bases obtained were then converted to the corresponding hydrochlorides. Yields and NMR data of their free bases are listed below.
Ex-
am- NMR data (400 MHz, measured as
ple Structure Yield free bases, CDCl3) δ
88
Figure US06867221-20050315-C00226
 		63% 1.70-1.82(m, 2H), 1.83-1.90(m, 2H), 2.14-2.23(m, 21-1), 2.94- 3.01(m, 2H), 3.57(s, 2H), 3.73(s, 3H), 3.76-3.88(m, 1H), 3.89(s, 3H), 3.90(s, 3H), 3.93(s, 6H), 3.96 (s, 6H), 4.53(s, 2H), 6.26-6.35(m, 3H), 7.11(dd, 1H, J=8.3Hz, 8.3 Hz), 7.12-7.14(m, 1H), 7.15(s,
# 2H), 7.20(d, 1H, J=5.1Hz), 7.22 (s, 2H), 7.55(s, 1H), 7.58(s, 1H), 8.55(d, 1H, J=4.9Hz), 8.59(d, 1H, J=4.9Hz).
89
Figure US06867221-20050315-C00227
 		72% 1.67-1.90(m, 4H), 2.13-2.22(m, 2H), 2.94-3.04(m, 2H), 3.59(s, 2H), 3.74(s, 3H), 3.77-3.87(m, 1H), 3.89(s, 3H), 3.89(s, 3H), 3.92(s, 6H), 3.93(s, 6H), 4.52(s, 2H), 6.27(dd, 1H, J=2.4Hz, 2.4 Hz), 6.29-6.34(m, 2H), 6.75(s, 2H), 7.08-7.17(m, 4H), 7.54(s,
# 1H), 7.75(s, 1H), 8.50(d, 1H, J=1.8Hz), 8.54(d, 1H, J=5.1Hz), 8.69(d, 1H, J=2.0Hz).
90
Figure US06867221-20050315-C00228
 		60% 1.68-1.90(m, 4H), 2.09-2.19(m, 2H), 2.97-3.06(m, 2H), 3.58(s, 2H), 3.73(s, 3H), 3.76-3.87(m, 1H), 3.89(s, 6H), 3.92(s, 6H), 3.92(s, 6H), 4.52(s, 2H), 6.25- 6.35(m, 3H), 6.76(s, 2H), 6.78- 7.17(m, 4H), 7.25-7.32(m, 1H), 7.37(dd, 1H, J=7.4Hz, 7.4Hz), 7.41-7.47(m, 2H), 7.54(s, 1H),
# 8.54(d, 1H, J=5.1Hz).
91
Figure US06867221-20050315-C00229
 		50% 1.80-1.93(m, 4H), 2.13-2.32(m, 2H), 2.87-3.10(m, 2H), 3.60(s, 1H), 3.69-3.85(m, 1H), 3.73(s, 3H), 3.88(s, 3H), 3.89(s, 6H), 3.90(s, 3H), 3.96(s, 6H), 4.57(s, 2H), 6.29-6.34(m, 2H), 6.37(dd, 1H, J=8.2Hz, 8.1Hz), 6.67(s, 2H), 7.11(dd, 1H, J=8.6Hz, 8.6
# Hz), 7.20-7.28(m, 3H), 7.58-7.72 (m, 1H), 7.68(s, 1H), 8.50(d, 1H, J=1.8Hz), 8.60(d, 1H, J=4.7Hz), 8.65(d, 1H, J=2.0Hz).
92
Figure US06867221-20050315-C00230
 		35% 1.70-1.90(m, 4H), 2.12-2.25(m, 2H), 2.95-3.03(m, 2H), 3.59(s, 2H), 3.72-3.97(m, 1H), 3.73(s, 3H), 3.88(s, 3H), 3.89(s, 6H), 3.90(s, 3H), 3.93(s, 6H), 4.54(s, 2H), 6.25-6.38(m, 2H), 6.36(d, 1H, J=8.4Hz, 8.4Hz), 6.67(s, 2H), 6.75(s, 2H), 7.11(dd, 1H,
# J=8.4Hz), 7.66(s, 1H), 8.49(s, 1H), 8.50(d, 1H, J=1.8Hz), 8.64 (d, 1H, J=2.0Hz), 8.70(d, 1H, J=1.9Hz).
93
Figure US06867221-20050315-C00231
 		86% 1.73-1.93(m, 4H), 2.13-2.23(m, 2H), 2.94-3.02(m, 2H), 3.57(s, 2H), 3.73(s, 3H), 3.77-3.87(m, 1H), 3.88(s, 3H), 3.88(s, 6H), 3.90(s, 3H), 3.96(s, 6H), 4.56 (s, 2H), 6.27(dd, 1H, J=8.0Hz, 2.2 Hz), 6.31(dd, 1H, J=2.2Hz, 2.2 Hz), 6.36(dd, 1H, J=8.2Hz, 2.2
# Hz), 6.71(s, 2H), 7.09(dd, 1H, J=8.1Hz, 8.1Hz), 7.18-7.28(m, 4H), 7.34(dd, 1H, J=7.4Hz, 7.4 Hz), 7.38(d, 1H, J=7.6Hz), 7.42 (s, 1H), 7.59(s, 1H), 8.59(d, 1H, J=4.9Hz).
94
Figure US06867221-20050315-C00232
 		56% 1.72-1.92(m, 4H), 2.10-2.23(m, 2H), 2.92-3.60(m, 2H), 3.59(s, 2H), 3.72(s, 3H), 3.77-3.89(m, 1H), 3.87(s, 3H), 3.88(s, 6H), 3.93(s, 6H), 4.55(s, 2H), 6.27 (dd, 1H, J=8.0Hz, 2.2Hz), 6.31 (dd, 1H, J=2.1Hz, 2.1Hz), 6.36 (dd, 1H, J=8.4Hz, 2.4Hz), 6.70
# (s, 2H), 6.75(s, 2H), 7.09(dd, 1H, J=8.2Hz, 8.2Hz), 7.22(d, 1H, J=7.4Hz), 7.33(dd, 1H, J=7.4Hz, 7.4Hz), 7.38(d, 1H, J=7.8Hz), 7.40(s, 1H), 7.77(s, 1H), 8.50(d, 1H, J=1.8Hz), 8.69(d, 1H, J=1.8 Hz).
95
Figure US06867221-20050315-C00233
 		77% 1.66-1.89(m, 4H), 2.08-2.18(m, 2H), 2.95-3.05(m, 2H), 3.58(s, 2H), 3.72(s, 3H), 3.75-3.84(m, 1H), 3.87(s, 3H), 3.88(s, 6H), 3.89(s, 3H), 3.92(s, 6H), 4.55(s, 2H), 6.26(dd, 1H, J=8.0Hz, 2.2 Hz), 6.30(dd, 1H, J=2.2Hz, 2.2 Hz), 6.36(dd, 1H, J=8.3Hz, 2.2
# Hz), 6.70(s, 2H), 6.76(s, 2H), 7.08(dd, 1H, J=8.3Hz, 8.3Hz), 7.22(d, 1H, J=7.3Hz), 7.27-7.47 (m, 7H).
PREPARATION EXAMPLE 122 Synthesis of 4-(o-anisidino)-1-(tert-butoxycarbonyl)piperidine
Figure US06867221-20050315-C00234
1-(tert-Butoxycarbonyl)-4-piperidone (4.78 g) and o-anisidine (2.96 g) were condensed in the same manner as described in Preparation Example 37 to give the title compound.
Yield: 2.61 g (36%). 1H-NMR (400 MHz, CDCl3) δ: 1.31-1.41 (m, 2H), 1.47 (s, 9H), 2.00-2.08 (m, 2H), 2.90-3.01 (m, 2H), 3.38-3.47 (m, 1H), 3.83 (s, 3H), 4.00-4.21 (m, 2H), 6.60-6.69 (m, 2H), 6.76-6.89 (m, 2H).
PREPARATION EXAMPLE 123 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(2-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00235
4-(o-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 763 mg (68%). 1H-NMR (400 MHz, CDCl3) δ: 1.41-1.58 (m, 2H), 1.44 (s, 9H), 1.81-1.91 (m, 2H), 2.62-2.78 (m, 2H), 3.29 (tt, 1H, J=7.6 Hz, 3.7 Hz), 3.86 (s, 3H), 3.89 (s, 3H), 3.95 (s, 6H), 4.06-4.16 (m, 2H), 4.37 (s, 2H), 6.80 (ddd, 1H, J=7.6 Hz, 7.6 Hz, 1.2 Hz), 6.87 (dd, 1H, J=8.5 Hz, 1.0 Hz), 7.00-7.06 (m, 2H), 7.14 (s, 2H), 7.20 (dd, 1H, J=4.9 Hz, 1.0 Hz), 7.61 (s, 1H), 8.49 (d, 1H, J=4.9 Hz).
PREPARATION EXAMPLE 124 Synthesis of 4-[N-(2-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00236
1-(tert-Butoxycarbonyl)-4-[N-(2-methoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine (763 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 701 mg (97%).
PREPARATION EXAMPLE 125 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(2-methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00237
4-(o-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 353 mg (31%). 1H-NMR (400 MHz, CDCl3) δ: 1.44 (s, 9H), 1.46-1.53 (m, 2H), 1.82-1.91 (m, 2H), 2.62-2.78 (m, 2H), 3.24-3.33 (m, 1H), 3.83 (s, 3H), 3.89 (s, 3H), 3.91 (s, 6H), 4.03-4.16 (m, 2H), 4.37 (s, 2H), 6.64 (s, 2H), 6.79 (ddd, 1H, J=7.6 Hz, 7.6 Hz, 1.2 Hz), 6.84 (dd, 1H, J=7.0 Hz, 1.2 Hz), 6.97-7.06 (m, 2H), 7.68 (dd, 1H, J=1.3 Hz, 1.3 Hz), 8.49 (d, 1H, J=2.0 Hz), 8.56 (d, 1H, J=2.2 Hz).
PREPARATION EXAMPLE 126 Synthesis of 4-[N-(2-methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00238
1-(tert-Butoxycarbonyl)-4-[N-(2-methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine (353 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 312 mg (93%).
PREPARATION EXAMPLE 127 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(2-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine
Figure US06867221-20050315-C00239
4-(o-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 1.12 g (100%). 1H-NMR (400 MHz, CDCl3) δ: 1.43 (s, 9H), 1.46-1.57 (m, 2H), 1.81-1.90 (m, 2H), 2.62-2.76 (m, 2H), 3.31 (tt, 1H, J=11.1 Hz, 3.3 Hz), 3.84 (s, 3H), 3.88 (s, 3H), 3.91 (s, 6H), 4.00-4.16 (m, 2H), 4.36 (s, 2H), 6.67 (s, 2H), 6.78 (t, 1H, J=7.3 Hz), 6.85 (d, 1H, J=7.9 Hz), 6.96-7.03 (m, 2H), 7.24-7.34 (m, 3H), 7.43 (s, 1H).
PREPARATION EXAMPLE 128 Synthesis of 4-[N-(2-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine hydrochloride
Figure US06867221-20050315-C00240
1-(tert-Butoxycarbonyl)-4-[N-(2-methoxyphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (1.12 g) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 987 mg (99%).
EXAMPLES 96 TO 101
These compounds were obtained by the condensation of amines obtained in Preparation Examples 124, 126 and 128 with chloride derivatives obtained in Preparation Examples 3 and 48. Free bases obtained were then converted to the corresponding hydrochlorides. Yields and NMR data of their free bases are listed below.
Ex-
am- NMR data (400 MHz, measured as
ple Structure Yield free bases, CDCl3) δ
96
Figure US06867221-20050315-C00241
 		73% 1.62-1.74(m, 2H), 1.82-1.90(m, 2H), 1.98-2.08(m, 2H), 2.86-2.94 (m, 2H), 3.13-3.22(m, 1H), 3.52 (s, 2H), 3.85(s, 3H), 3.89(s, 3H), 3.90(s, 3H), 3.94(s, 6H), 3.96(s, 6H), 4.40(s, 2H), 6.80(ddd, 1H, J=7.6Hz, 7.6Hz, 1.2Hz), 6.86 (dd, 1H, J=8.1Hz,1.2Hz), 6.98-
# 7.05(m, 1H), 7.14(s, 2H), 7.18 (dd, 1H, J=4.9Hz, 1.2Hz), 7.20- 7.24(m, 1H), 7.22(s, 2H), 7.58(s, 1H), 7.62(s, 1H), 8.49(d, 1H, J=4.9Hz , 8.57(d, 1H, J=5.2Hz).
97
Figure US06867221-20050315-C00242
 		55% 1.60-1.73(m, 4H), 1.82-1.93(m, 2H), 1.98-2.07(m, 2H), 2.87-2.97 (m, 2H), 3.12-3.22(m, 1H), 3.54 (s, 2H), 3.85(s, 3H), 3.89(s, 3H), 3.90(s, 3H), 3.93(s, 6H), 3.94(s, 6H), 4.39(s, 2H), 6.75(s, 2H), 6.79(dd, 1H, J=7.4Hz, 7.4Hz), 6.86(d, 1H, J=7.8Hz), 6.97-7.05
# (m, 2H), 7.13(s, 2H), 7.20(d, 1H, J=4.7Hz), 7.61(s, 1H), 7.75(s, 1H), 8.46-8.50(m, 2H), 8.68(d, 1H, J=2.0Hz).
98
Figure US06867221-20050315-C00243
 		29% 1.64-1.82(m, 2H), 1.84-1.97(m, 2H), 2.00-2.15(m, 2H), 2.84-3.01 (m, 2H), 3.13-3.27(m, 1H), 3.56 (s, 2H), 3.82(s, 3H), 3.88(s, 3H), 3.90(s, 3H), 3.91(s, 6H), 3.96(s, 6H), 4.40(s, 2H), 6.63(s, 2H), 6.75-6.88(m, 2H), 6.97-7.04(m, 2H), 7.19(d, 1H, J=4.3Hz), 7.25
# (s, 2H), 7.58-7.73(m, 2H), 8.50 (d, 1H, J=1.6Hz), 8.56(d, 1H, J=2.2Hz), 8.58(d, 1H, J=4.9Hz).
99
Figure US06867221-20050315-C00244
 		30% 1.62-1.75(m, 2H), 1.83-1.94(m, 2H), 1.95-2.11(m, 2H), 2.84-3.01 (m, 2H), 3.12-3.23(m, 1H), 3.55 (s, 2H), 3.82(s, 3H), 3.88(s, 3H), 3.90(s, 3H), 3.90(s, 6H), 3.93(s, 6H), 4.39(s, 2H), 6.63(s, 2H), 6.70-6.86(m, 4H), 6.94-7.06(m, 2H), 7.68(s, 1H), 7.76(s, 1H),
# 8.47(d, 1H, J=1.7Hz), 8.49(d, 1H, J=1.7Hz), 8.55(d, 1H, J=2.2 Hz), 8.69(s, 1H).
100 
Figure US06867221-20050315-C00245
 		67% 1.64-1.79(m, 2H), 1.85-1.93(m, 2H), 1.99-2.09(m, 2H), 2.86-2.95 (m, 2H), 3.16-3.26(m, 1H), 3.52 (s, 2H), 3.84(s, 3H), 3.88(s, 3H), 3.90(s, 6H), 3.96(s, 6H), 4.40(s, 2H), 6.67(s, 2H), 6.78(dd, 1H, J=7.4Hz, 7.4Hz), 6.85(d, 1H, J=8.2Hz), 6.97(dd, 1H, J=7.8Hz,
# 7.8Hz), 7.02(dd, 1H, J=7.8, 1.6 Hz), 7.17-7.33(m, 6H), 7.44(s, 1H), 7.59(s, 1H), 8.57(d, 1H, J=5.1Hz).
101 
Figure US06867221-20050315-C00246
 		55% 1.62-1.77(m, 2H), 1.82-1.94(m, 2H), 1.98-2.08(m, 2H), 2.86-2.96 (m, 2H), 3.16-3.26(m, 1H), 3.54 (s, 2H), 3.83(s, 3H), 3.87(s, 3H), 3.90(s, 9H), 3.93(s, 6H), 4.39(s, 2H), 6.66(s, 2H), 6.73-6.80(m, 3H), 6.84(d, 1H, J=7.8Hz), 6.97 (dd, 1H, J=7.8Hz, 7.8Hz), 7.01
# (d, 1H, J=7.8Hz), 7.23-7.32(m, 3H), 7.43(s, 1H), 7.77(s, 1H), 8.47(d, 1H, J=1.4Hz), 8.68(d, 1H, J=1.8Hz).
PREPARATION EXAMPLE 129 Synthesis of 1-(tert-butoxycarbonyl)-4-[(2,3-dimethoxyphenyl)amino]piperidine
Figure US06867221-20050315-C00247
1-(tert-Butoxycarbonyl)-4-piperidone (4.78 g) and 2,3-dimethoxyaniline (3.68 g) were condensed in the same manner as described in Preparation Example 37 to give the title compound.
Yield: 3.18 g (39%). 1H-NMR (400 MHz, CDCl3) δ: 1.29-1.42 (m, 2H), 1.45 (s, 9H), 1.97-2.03 (m, 2H), 2.92 (dt, 2H, J=13.5 Hz, 2.2 Hz), 3.38 (dt, 1H, J=13.8 Hz, 4.1 Hz), 3.77 (s, 3H), 3.82 (s, 3H), 3.99-4.03 (m, 2H), 4.17 (m, 1H), 6.27-6.32 (m, 2H), 6.88 (t, 1H, J=8.4 Hz).
PREPARATION EXAMPLE 130 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(2,3-dimethoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00248
1-(tert-Butoxycarbonyl)-4-[(2,3-dimethoxyphenyl)amino]piperidine (673 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 613 mg (52%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.56-1.70 (m, 2H), 1.84-1.91 (m, 2H), 2.62-2.76 (m, 2H), 3.58 (tt, 1H, J=11.8 Hz, 3.6 Hz), 3.83 (s, 3H), 3.89 (s, 6H), 3.93 (s, 6H), 4.08-4.25 (m, 2H), 4.35 (s, 2H), 6.56-6.63 (m, 2H), 6.86 (t, 1H, J=8.3 Hz), 7.14 (s, 2H), 7.17 (dd, 1H, J=5.1 Hz, 1.2 Hz), 7.62 (s, 1H), 8.50 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 131 Synthesis of 4-[N-(2,3-dimethoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00249
1-(tert-Butoxycarbonyl)-4-[N-(2,3-dimethoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine (613 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 512 mg (88%).
EXAMPLE 102 Synthesis of 4-[N-(2,3-dimethoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00250
4-[N-(2,3-Dimethoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine dihydrochloride (113 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (59 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as light yellow powder after converting a free base to a trihydrochloride.
Yield: 21 mg (12%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.76-1.96 (m, 4H), 2.00-2.13 (m, 2H), 2.86-3.00 (m, 2H), 3.42-3.60 (m, 1H), 3.54 (s, 2H), 3.82 (s, 3H), 3.88 (s, 3H), 3.90 (s, 3H), 3.97 (s, 6H), 4.41 (s, 2H), 6.57 (d, 1H, J=8.0 Hz), 6.62 (d, 1H, J=8.2 Hz), 6.85 (dd, 1H, J=8.4 Hz, 8.4 Hz), 7.11-7.29 (m, 6H), 7.59 (s, 1H), 7.63 (s, 1H), 8.50 (d, 1H, J=4.9 Hz), 8.59 (d, 1H, J=4.9 Hz).
PREPARATION EXAMPLE 132 Synthesis of 1-(tert-butoxycarbonyl)-4-[[4-(trifluoromethoxy)phenyl]amino]piperidine
Figure US06867221-20050315-C00251
1-(tert-Butoxycarbonyl)-4-piperidone (5.00 g) and 4-(trifluoromethoxy)aniline (4.23 g) was treated in the same manner as described in Preparation Example 37 to give white powder of the title compound.
Yield: 5.22 g (60%). 1H-NMR (400 MHz, CDCl3) δ: 1.25-1.40 (m, 2H), 1.47 (s, 9H), 1.98-2.08 (m, 2H), 2.83-2.98 (m, 2H), 3.34-3.43 (m, 1H), 3.97-4.12 (m, 2H), 6.58 (d, 2H, J=8.8 Hz), 7.03 (d, 2H, J=8.8 Hz).
PREPARATION EXAMPLE 133 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[4-(trifluoromethoxy)phenyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00252
1-(tert-Butoxycarbonyl)-4-[[4-(trifluoromethoxy)phenyl]amino]piperidine (721 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 543 mg (44%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.52-1.66 (m, 2H), 1.81-1.91 (m, 2H), 2.73-2.88 (m, 2H), 3.88-3.99 (m, 1H), 3.89 (s, 3H), 3.93 (s, 6H), 4.15-4.34 (m, 2H), 4.48 (s, 2H), 6.68 (d, 2H, J=9.2 Hz), 7.07 (d, 2H, J=8.6 Hz), 7.12 (dd, 1H, J=5.2 Hz, 1.3 Hz), 7.15 (s, 2H), 7.52 (s, 1H), 8.58 (d, 1H, J=5.2 Hz).
PREPARATION EXAMPLE 134 Synthesis of 4-[N-[4-(trifluoromethoxy)phenyl]-N-[[2-(3,4,5-trimethoxyphenyl) pyridin-4-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00253
1-(tert-Butoxycarbonyl)-4-[N-[4-(trifluoromethoxy)phenyl]-N-[[2-(3,4,5-trime thoxyphenyl)pyridin-4-yl]methyl]amino]piperidine (543 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 481 mg (93%).
PREPARATION EXAMPLE 135 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[4-(trifluoromethoxy)phenyl]-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00254
1-(tert-Butoxycarbonyl)-4-[[4-(trifluoromethoxy)phenyl]amino]piperidine (721 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 201 mg (16%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.54-1.67 (m, 2H), 1.82-1.90 (m, 2H), 2.74-2.86 (m, 2H), 3.84-3.91 (m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 4.16-4.30 (m, 2H), 4.52 (s, 2H), 6.67 (s, 2H), 6.72 (d, 2H, J=9.4 Hz), 7.06 (d, 2H, J=8.4 Hz), 7.64 (t, 1H, J=2.1 Hz), 8.49 (d, 1H, J=2.2 Hz), 8.68 (d, 1H, J=2.1 Hz).
PREPARATION EXAMPLE 136 Synthesis of 4-[N-[4-(trifluoromethoxy)phenyl]-N-[[3-(3,4,5-trimethoxyphenyl) pyridin-5-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00255
1-(tert-Butoxycarbonyl)-4-[N-[4-(trifluoromethoxy)phenyl]-N-[[3-(3,4,5-trime thoxyphenyl)pyridin-5-yl]methyl]amino]piperidine (201 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 185 mg (96%).
PREPARATION EXAMPLE 137 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[4-(trifluoromethoxy)phenyl]-N-[3-(3,4,5-trimethoxyphen yl)benzyl]amino)piperidine
Figure US06867221-20050315-C00256
1-(tert-Butoxycarbonyl)-4-[[4-(trifluoromethoxy)phenyl]amino]piperidine (721 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 1.06 mg (86%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.56-1.68 (m, 2H), 1.83-1.90 (m, 2H), 2.71-2.86 (m, 2H), 3.87-3.90 (m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 4.16-4.29 (m, 2H), 4.51 (s, 2H), 6.70 (d, 2H, J=9.3 Hz), 6.70 (s, 2H), 7.04 (d, 2H, J=8.5 Hz), 7.22 (d, 1H, J=7.8 Hz), 7.34-7.44 (m, 3H).
PREPARATION EXAMPLE 138 Synthesis of 4-[N-[4-(trifluoromethoxy)phenyl]-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine hydrochloride
Figure US06867221-20050315-C00257
1-(tert-Butoxycarbonyl)-4-[N-[4-(trifluoromethoxy)phenyl]-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (1.06 g) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 795 mg (84%).
EXAMPLES 103 TO 110
These compounds were obtained by the condensation of amines obtained in Preparation Examples 134, 136 and 138 with chloride derivatives obtained in Preparation Examples 3, 42 and 48. Free bases obtained were then converted to the corresponding hydrochlorides. Yields and NMR data of their free bases are listed below.
Ex-
am- NMR data (400 MHz, measured as
ple Structure Yield free bases, CDCl3) δ
103
Figure US06867221-20050315-C00258
 		70% 1.71-1.90(m, 4H), 2.15-2.23(m, 2H), 2.95-3.02(m, 2H) 3.58(s, 2H), 3.76-3.85(m, 1H), 3.89(s, 3H), 3.90(s, 3H), 3.92(s, 6H), 3.96(s, 6H), 4.54(s, 2H), 6.66(d, 2H, J=9.3Hz), 7.05(d, 2H, J=8.5 Hz), 7.13(dd, 1H, J=5.1Hz, 1.2 Hz), 7.14(s, 2H), 7.20(dd, 1H,
# J=4.9Hz, 1.2Hz), 7.22(s, 2H), 7.53(s, 1H), 7.59(s, 1H), 8.57(d, 1H, J=4.9Hz), 8.59(d, 1H, J=5.2 Hz).
104
Figure US06867221-20050315-C00259
 		48% 1.68-1.92(m, 4H), 2.13-2.25(m, 2H), 2.95-3.06(m, 2H), 3.60(s, 2H), 3.75-3.87(m, 1H), 3.89(s, 3H), 3.90(s, 3H), 3.91(s, 6H), 3.93(s, 6H), 4.52(s, 2H), 6.65(d, 2H, J=9.4Hz), 6.75(s, 2H), 7.05 (d, 2H, J=9.2Hz), 7.12(d, 1H, J=5.1Hz), 7.14(s, 2H), 7.52(s,
# 1H), 7.76(s, 1H), 8.51(d, 1H, J=1.8Hz), 8.57(d, 1H, J=5.1Hz), 8.70(d, 1H, J=2.1Hz).
105
Figure US06867221-20050315-C00260
 		69% 1.70-1.89(m, 4H), 2.10-2.19(m, 2H), 2.98-3.08(m, 2H), 3.59(s, 2H), 3.72-3.84(m, 1H), 3.89(s, 6H), 3.92(s, 6H), 3.92(s, 6H), 4.52(s, 2H), 6.65(d, 2H, J=9.4 Hz), 6.76(s, 2H), 7.04(d, 2H, J=8.6Hz), 7.11(d, 1H, J=5.1Hz), 7.14(s, 2H), 7.25-7.33(m, 1H),
# 7.37(dd, 1H, J=7.4Hz, 7.4Hz), 7.41-7.48(m, 2H), 7.51(s, 1H), 8.56(d, 1H, J=5.1Hz).
106
Figure US06867221-20050315-C00261
 		41% 1.73-1.93(m, 4H), 2.12-2.26(m, 2H), 2.93-3.07(m, 2H), 3.53-3.65 (m, 2H), 3.74-3.84(m, 1H), 3.88 (s, 9H), 3.90(s, 3H), 3.96(s, 6H), 4.58(s, 2H), 6.66(s, 2H), 6.69(d, 2H, J=9.2Hz), 7.05(d, 2H, J=8.8 Hz), 7.18-7.29(m, 3H), 7.59(br, 1H), 7.64(s, 1H), 8.49(s, 1H),
# 8.60(d, 1H, J=5.3Hz), 8.67(d, 1H, J=2.0Hz).
107
Figure US06867221-20050315-C00262
 		28% 1.72-1.91(m, 4H), 2.12-2.28(m, 2H), 2.94-3.06(m, 2H), 3.60(s, 2H), 3.76-3.82(m, 1H), 3.88(s, 9H), 3.90(s, 3H), 3.93(s, 6H), 4.56(s, 2H), 6.65(s, 2H), 6.69(d, 2H, J=9.2Hz), 6.75(s, 2H), 7.05 (d, 2H, J=8.8Hz), 7.63(s, 1H), 7.76(s, 1H), 8.48(d, 1H, J=1.8
# Hz), 8.51(d, 1H, J=1.8Hz), 8.66 (d, 1H, J=2.2Hz), 8.70(d, 1H, J=2.2Hz).
108
Figure US06867221-20050315-C00263
 		78% 1.76-1.91(m, 4H), 2.14-2.23(m, 2H), 2.94-3.03(m, 2H), 3.57(s, 2H), 3.75-3.84(m, 1H), 3.87(s, 9H), 3.90(s, 3H), 3.96(s, 6H), 4.56(s, 2H), 6.65-6.72(m, 4H), 7.03(d, 2H, J=8.8Hz), 7.18-7.24 (m, 4H), 7.33-7.43(m, 3H), 7.59 (s, 1H), 8.59(d, 1H, J=4.9Hz).
109
Figure US06867221-20050315-C00264
 		 5% 1.72-1.90(m, 4H), 2.12-2.21(m, 2H), 2.94-3.03(m, 2H), 3.59(s, 2H), 3.73-3.86(m, 1H), 3.87(s, 9H), 3.90(s, 3H), 3.93(s, 6H), 4.54(s, 2H), 6.66-6.70(m, 4H), 6.75(s, 2H), 7.03(d, 2H, J=9.0 Hz), 7.21(d, 1H, J=7.2Hz), 7.32- 7.41(m, 3H), 7.76(s, 1H), 8.50
# (d, 1H, J=1.6Hz), 8.69(d, 1H, J=1.6Hz).
110
Figure US06867221-20050315-C00265
 		62% 1.72-1.89(m, 4H), 2.08-2.20(m, 2H), 2.97-3.07(m, 2H), 3.59(s, 2H), 3.73-3.83(m, 1H), 3.87(s, 9H), 3.89(s, 3H), 3.92(s, 6H), 4.55(s, 2H), 6.67(d, 2H, J=9.3 Hz), 6.69(s, 2H), 6.76(s, 2H), 7.02(d, 2H, J=8.6Hz), 7.20(d, 1H, J=7.6 Hz), 7.25-7.47(m, 7H).
PREPARATION EXAMPLE 139 Synthesis of 1-(tert-butoxycarbonyl)-4-[[4-(methylthio)phenyl]amino]piperidine
Figure US06867221-20050315-C00266
1-(tert-Butoxycarbonyl)-4-piperidone (5.00 g) and 4-(methylthio)aniline (3.33 g) was treated in the same manner as described in Preparation Example 37 to give white powder of the title compound.
Yield: 3.80 g (49%). 1H-NMR (400 MHz, CDCl3) δ: 1.26-1.38 (m, 2H), 1.46 (s, 9H), 1.98-2.06 (m, 2H), 2.41 (s, 3H), 2.88-2.97 (m, 2H), 3.36-3.45 (m, 2H), 3.48-3.56 (br, 1H), 3.96-4.12 (m, 2H), 6.55 (d, 2H, J=8.8 Hz), 7.21 (d, 2H, J=8.8 Hz).
PREPARATION EXAMPLE 140
Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[4-(methylthio)phenyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00267
1-(tert-Butoxycarbonyl)-4-[[4-(methylthio)phenyl]amino]piperidine (644 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 671 mg (58%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.50-1.66 (m, 2H), 1.81-1.89 (m, 2H), 2.40 (s, 3H), 2.74-2.87 (m, 2H), 3.88-3.94 (m, 1H), 3.90 (s, 3H), 3.94 (s, 6H), 4.15-4.29 (m, 2H), 4.48 (s, 2H), 6.67 (d, 2H, J=9.0 Hz), 7.11-7.18 (m, 1H), 7.16 (s, 2H), 7.22 (d, 2H, J=6.6 Hz), 7.54 (s, 1H), 8.57 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 141 Synthesis of 4-[N-[4-(methylthio)phenyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00268
1-(tert-Butoxycarbonyl)-4-[N-[4-(methylthio)phenyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine (671 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 602 mg (94%).
PREPARATION EXAMPLE 142 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[4-(methylthio)phenyl]-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00269
1-(tert-Butoxycarbonyl)-4-[[4-(methylthio)phenyl]amino]piperidine (645 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 312 mg (27%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.53-1.63 (m, 2H), 1.83-1.89 (m, 2H), 2.40 (s, 3H), 2.73-2.85 (m, 2H), 3.87-3.91 (m, 1H), 3.88 (s, 3H), 3.90 (s, 6H), 4.16-4.30 (m, 2H), 4.50 (s, 2H), 6.67 (s, 2H), 6.71 (d, 2H, J=9.0 Hz), 7.21 (d, 2H, J=9.0 Hz), 7.64 (s, 1H), 8.48 (d, 1H, J=2.2 Hz), 8.66 (d, 1H, J=2.1 Hz).
PREPARATION EXAMPLE 143 Synthesis of 4-[N-[4-(methylthio)phenyl]-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00270
1-(tert-Butoxycarbonyl)-4-[N-[4-(methylthio)phenyl]-N-[[3-(3,4,5-trimethoxy phenyl)pyridin-5-yl]methyl]amino]piperidine (312 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 251 mg (84%).
PREPARATION EXAMPLE 144 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[4-(methylthio)phenyl]-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine
Figure US06867221-20050315-C00271
1-(tert-Butoxycarbonyl)-4-[[4-(methylthio)phenyl]amino]piperidine (645 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 1.10 g (95%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.55-1.68 (m, 2H), 1.81-1.90 (m, 2H), 2.39 (s, 3H), 2.73-2.86 (m, 2H), 3.87-3.91 (m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 4.15-4.29 (m, 2H), 4.50 (s, 2H), 6.68-6.73 (m, 4H), 7.19-7.24 (m, 3H), 7.33-7.43 (m, 3H).
PREPARATION EXAMPLE 145 Synthesis of 4-[N-[4-(methylthio)phenyl]-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine hydrochloride
Figure US06867221-20050315-C00272
1-(tert-Butoxycarbonyl)-4-[N-[4-(methylthio)phenyl]-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (1.10 g) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 866 mg (89%).
EXAMPLES 111 TO 118
These compounds were obtained by the condensation of amines obtained in Preparation Examples 141, 143 and 145 with chloride derivatives obtained in Preparation Examples 3, 42 and 48. Free bases obtained were then converted to the corresponding hydrochlorides. Yields and NMR data of their free bases are listed below.
Ex-
am- NMR data (400 MHz, measured
ple Structure Yield as free bases, CDCl3) δ
111
Figure US06867221-20050315-C00273
 		40% 1.70-1.90(m, 4H), 2.14-2.26(m, 2H), 2.40(s, 3H), 2.94-3.04(m, 2H), 3.58(s, 2H), 3.76-3.88(m, 1H), 3.89(s, 3H), 3.90(s, 3H), 3.93(s, 6H), 3.96(s, 6H), 4.53(s, 2H), 6.66(d, 2H, J=9.0Hz), 7.11- 7.24(m, 8H), 7.54(s, 1H), 7.59(s, 1H), 8.56(d, 1H, J=5.1Hz), 8.59
# (d, 1H, J=5.1Hz).
112
Figure US06867221-20050315-C00274
 		53% 1.66-1.90(m, 4H), 2.12-2.24(m, 2H), 2.40(s, 3H), 2.94-3.05(m, 2H), 3.59(s, 2H), 3.73-3.88(m, 1H), 3.89(s, 3H), 3.90(s, 3H), 3.92(s, 6H), 3.93(s, 6H), 4.51(s, 2H), 6.65(d, 2H, J=8.8Hz), 6.75 (s, 2H), 7.12(d, 1H, J=4.9Hz), 7.14(s, 2H), 7.21(d, 2H, J=8.8
# Hz), 7.53(s, 1H), 7.76(s, 1H), 8.50(d, 1H, J=1.9Hz), 6.55(d, 1H, J=4.9Hz), 8.69(d, 1H, J=1.4 Hz).
113
Figure US06867221-20050315-C00275
 		53% 1.68-1.89(m, 4H), 2.10-2.20(m, 2H), 2.39(s, 3H), 2.98-3.07(m, 2H), 3.58(s, 2H), 3.75-3.87(m, 1H), 3.89(s, 6H), 3.92(s, 6H), 3.92(s, 6H), 4.51(s, 2H), 6.65(d, 2H, J=9.0Hz), 6.76(s, 2H), 7.11 (d, 1H, J=5.1Hz), 7.14(s, 2H), 7.21(d, 2H, J=8.8Hz), 7.29(d,
# 1H, J=7.4Hz), 7.37(dd, 1H, J=7.6 Hz, 7.6Hz), 7.42-7.49(m, 2H), 7.52(s, 1H), 8.54(d, 1H, J=4.9 Hz).
114
Figure US06867221-20050315-C00276
 		50% 1.57-2.00(m, 4H), 2.12-2.30(m, 2H), 2.39(s, 3H), 2.90-3.13(m, 2H), 3.50-3.74(m, 2H), 3.75-3.86 (m, 1H), 3.88(s, 3H), 3.89(s, 3H), 3.90(s, 6H), 3.97(s, 6H), 4.57(s, 2H), 6.66(s, 2H), 6.70(d, 2H, J=9.0Hz), 7.17-7.30(m, 5H), 7.66(br, 2H), 8.48(s, 1H), 8.58-
# 8.70(m, 2H).
115
Figure US06867221-20050315-C00277
 		59% 1.68-1.92(m, 4H), 2.12-2.27(m, 2H), 2.39(s, 3H), 2.94-3.08(m, 2H), 3.60(s, 2H), 3.74-3.83(m, 1H), 3.88(s, 3H), 3.89(s, 6H), 3.90(s, 3H), 3.93(s, 6H), 4.55(s, 2H), 6.66(s, 2H), 6.69(d, 2H, J=8.8Hz), 6.73-6.80(m, 2H), 7.20 (d, 2H, J=8.8Hz), 7.64(s, 1H),
# 7.77(br, 1H), 8.48(s, 1H), 8.50(s, 1H), 8.65(s, 1H), 8.71(s, 1H).
116
Figure US06867221-20050315-C00278
 		85% 1.76-1.93(m, 4H), 2.14-2.24(m, 2H), 2.39(s, 3H), 2.94-3.03(m, 2H), 3.57(s, 2H), 3.76-3.86(m, 1H), 3.88(s, 6H), 3.90(s, 3H), 3.96(s, 6H), 4.55(s, 2H), 6.67- 6.73(m, 4H), 7.18-7.29(m, 6H), 7.34(dd, 1H, J=7.6Hz, 7.6Hz), 7.37-7.44(m, 2H), 7.59(s, 1H),
# 8.59(d, 1H, J=4.9Hz).
117
Figure US06867221-20050315-C00279
 		53% 1.72-1.90(m, 4H), 2.12-2.22(m, 2H), 2.39(s, 3H), 2.95-3.05(m, 2H), 3.59(s, 2H), 3.74-3.85(m, 1H), 3.87(s, 3H), 3.88(s, 6H), 3.89(s, 3H), 3.93(s, 6H), 4.54(s, 2H), 6.67-6.70(m, 4H), 6.75(s, 2H), 7.19-7.23(m, 3H), 7.33(dd, 1H, J=7.4Hz, 7.4Hz), 7.36-7.40
# (m, 2H), 7.76(s, 1H), 8.50(d, 1H, J=1.8Hz), 8.69(s, 1H).
118
Figure US06867221-20050315-C00280
 		83% 1.72-1.90(m, 4H), 2.09-2.20(m, 2H), 2.38(s, 3H), 2.97-3.06(m, 2H), 3.58(s, 2H), 3.73-3.84(m, 1H), 3.87(s, 3H), 3.88(s, 3H), 3.89(s, 6H), 3.92(s, 6H), 4.54(s, 2H), 6.66-6.71(m, 4H), 6.76(s, 2H), 7.18-7.24(m, 3H), 7.26-7.48 (m, 7H).
PREPARATION EXAMPLE 146 Synthesis of 1-(tert-butoxycarbonyl)-4-[(4-methylphenyl)amino]piperidine
Figure US06867221-20050315-C00281
1-(tert-Butoxycarbonyl)-4-piperidone (5.00 g) and p-toluidine (2.56 g) was treated in the same manner as described in Preparation Example 37 to give white powder of the title compound.
Yield: 5.79 g (83%). 1H-NMR (400 MHz, CDCl3) δ: 1.25-1.36 (m, 2H), 1.46 (s, 9H), 1.99-2.06 (m, 2H), 2.23 (s, 3H), 2.86-2.96 (m, 2H), 3.30-3.43 (m, 2H), 3.96-4.10 (m, 2H), 6.53 (d, 2H, J=8.4 Hz), 6.98 (d, 2H, J=8.0 Hz).
PREPARATION EXAMPLE 147 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-methylphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00282
1-(tert-Butoxycarbonyl)-4-[(4-methylphenyl)amino]piperidine (581 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 1.00 g (91%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.55-1.59 (m, 2H), 1.81-1.90 (m, 2H), 2.23 (s, 3H), 2.72-2.86 (m, 2H), 3.81-3.94 (m, 1H), 3.89 (s, 3H), 3.93 (s, 6H), 4.14-4.30 (m, 2H), 4.45 (s, 2H), 6.66 (d, 2H, J=8.6 Hz), 7.02 (d, 2H, J=8.2 Hz), 7.13-7.16 (m, 3H), 7.55 (s, 1H), 8.55 (d, 1H, J=8.1 Hz).
PREPARATION EXAMPLE 148 Synthesis of 4-[N-(4-methylphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00283
1-(tert-Butoxycarbonyl)-4-[N-(4-methylphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine (1.00 g) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 924 mg (97%).
PREPARATION EXAMPLE 149 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-methylphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00284
1-(tert-Butoxycarbonyl)-4-[(4-methylphenyl)amino]piperidine (581 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 426 mg (39%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.52-1.70 (m, 2H), 1.82-1.90 (m, 2H), 2.23 (s, 3H), 2.72-2.86 (m, 2H), 3.77-3.86 (m, 1H), 3.88 (s, 3H), 3.90 (s, 6H), 4.10-4.28 (m, 2H), 4.47 (s, 2H), 6.67 (s, 2H), 6.70 (d, 2H, J=8.6 Hz), 7.01 (d, 2H, J=8.2 Hz), 7.67 (dd, 1H, J=2.1 Hz, 2.1 Hz), 8.50 (d, 1H, J=2.0 Hz), 8.64 (d, 1H, J=2.2 Hz).
PREPARATION EXAMPLE 150 Synthesis of 4-[N-(4-methylphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00285
1-(tert-Butoxycarbonyl)-4-[N-(4-methylphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine (426 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 400 mg (99%).
PREPARATION EXAMPLE 151 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-methylphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine
Figure US06867221-20050315-C00286
1-(tert-Butoxycarbonyl)-4-[(4-methylphenyl)amino]piperidine (581 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 1.03 g (94%). 1H-NMR (400 MHz, CDCl3) δ: 1.44 (s, 9H), 1.50-1.66 (m, 2H), 1.83-1.90 (m, 2H), 2.23 (s, 3H), 2.72-2.85 (m, 2H), 3.82-3.92 (m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 4.11-4.30 (m, 2H), 4.47 (s, 2H), 6.68 (d, 2H, J=8.6 Hz), 6.71 (s, 2H), 7.00 (d, 2H, J=8.8 Hz), 7.23-7.27 (m, 1H), 7.32-7.44 (m, 3H).
PREPARATION EXAMPLE 152 Synthesis of 4-[N-(4-methylphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine hydrochloride
Figure US06867221-20050315-C00287
1-(tert-Butoxycarbonyl)-4-[N-(4-methylphenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (1.03 g) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 882 mg (97%).
EXAMPLES 119 TO 126
These compounds were obtained by the condensation of amines obtained in Preparation Examples 148, 150 and 152 with chloride derivatives obtained in Preparation Examples 3, 42 and 48. Free bases obtained were then converted to the corresponding hydrochlorides. Yields and NMR data of their free bases are listed below.
Ex-
am- NMR data (400 MHz, measured
ple Structure Yield as free bases, CDCl3) δ
119
Figure US06867221-20050315-C00288
 		66% 1.70-1.82(m, 2H), 1.83-1.91(m, 2H), 2.13-2.25(m, 2H), 2.23(s, 3H), 2.96-3.02(m, 2H), 3.57(s, 2H), 3.73-3.83(m, 1H), 3.89(s, 3H), 3.90(s, 3H), 3.93(s, 6H), 3.96(s, 6H), 4.50(s, 2H), 6.64 (d, 2H, J=8.8Hz), 7.01(d, 2H, J=8.5Hz), 7.13-7.17(m, 3H),
# 7.20(d, 1H, J=4.9Hz), 7.22(s, 2H), 7.56(s, 1H), 7.59(s, 1H), 8.54(d, 1H, J=5.1Hz), 8.59(d, 1H, J=4.9Hz).
120
Figure US06867221-20050315-C00289
 		41% 1.60-1.91(m, 4H), 2.12-2.24(m, 2H), 2.23(s, 3H), 2.95-3.05(m, 2H), 3.59(s, 2H), 3.73-3.83(m, 1H), 3.89(s, 3H), 3.89(s, 3H), 3.92(s, 6H), 3.93(s, 6H), 4.49 (s, 2H), 6.63(d, 2H, J=8.6Hz), 6.75(s, 2H), 7.00(d, 2H, J=8.6 Hz), 7.13-7.16(m, 3H), 7.55(s,
# 1H), 7.76(s, 1H), 8.50(d, 1H, J=1.8Hz), 8.53(d, 1H, J=5.1 Hz), 8.70(s, 1H).
121
Figure US06867221-20050315-C00290
 		69% 1.67-1.80(m, 2H), 1.81-1.89(m, 2H), 2.09-2.20(m, 2H), 2.22(s, 3H), 2.98-3.06(m, 2H), 3.58(s, 2H), 3.72-3.81(m, 1H), 3.88(s, 3H), 3.89(s, 3H), 3.92(s, 6H), 3.92(s, 6H), 4.49(s, 2H), 6.63 (d, 2H, J=8.4Hz), 6.76(s, 2H), 7.00(d, 2H, J=8.6Hz), 7.12-
# 7.15(m, 3H), 7.26-7.32(m, 1H), 7.37 (dd, 1H, J=7.6Hz, 7.6Hz), 7.41-7.48(m, 2H), 7.55(s, 1H), 8.53(d, 1H, J=5.0Hz).
122
Figure US06867221-20050315-C00291
 		47% 1.55-2.00(m, 4H), 2.12-2.31(m, 2H), 2.22(s, 3H), 2.93-3.10(m, 2H), 3.60(br, 2H), 3.69-3.80(m, 1H), 3.88(s, 3H), 3.89(s, 6H), 3.90(s, 3H), 3.96(s, 6H), 4.53 (s, 2H), 6.66(s, 2H), 6.69(d, 2H, J=8.6Hz), 7.00(d, 2H, J=8.6Hz), 7.19-7.27(m, 4H),
# 7.68(s, 1H), 8.50(s, 1H), 8.60 (d, 1H, J=4.9Hz), 8.64(d, 1H, J=2.2Hz).
123
Figure US06867221-20050315-C00292
 		34% 1.67-1.98(m, 4H), 2.10-2.38(m, 2H), 2.22(s, 3H), 2.85-3.10(m, 2H), 3.53-3.67(s, 2H), 3.67-3.79 (m, 1H), 3.88(s, 3H), 3.89(s, 6H), 3.90(s, 3H), 3.93(s, 6H), 4.51(s, 2H), 6.66(s, 2H), 6.68 (d, 2H, J=8.8Hz), 6.76(s, 2H), 7.00(d, 2H, J=8.2Hz), 7.67(s,
# 1H), 7.77(br, 1H), 8.47-8.53(m, 2H), 8.63(d, 1H, J=2.0Hz), 8.70(s, 1H).
124
Figure US06867221-20050315-C00293
 		91% 1.73-1.92(m, 4H), 2.12-2.26(m, 2H), 2.21(s, 3H), 2.92-3.02(m, 2H), 3.57(s, 2H), 3.72-3.82(m, 1H), 3.87(s, 3H), 3.88(s, 6H), 3.90(s, 3H), 3.95(s, 6H), 4.53 (s, 2H), 6.67(d, 2H, J=7.8Hz), 6.70(s, 2H), 6.99(d, 2H, J=8.0 Hz), 7.18-7.25(m, 4H), 7.33
# (dd, 1H,J=7.4Hz, 7.4Hz), 7.38 (d, 1H, J=7.2Hz), 7.42(s, 1H), 7.59(s, 1H), 8.58(d, 1H, J=4.7 Hz).
125
Figure US06867221-20050315-C00294
 		74% 1.70-1.92(m, 4H), 2.10-2.28(m, 2H), 2.21(s, 3H), 2.92-3.06(m, 2H), 3.58(s, 2H), 3.72-3.82(m, 1H), 3.87(s, 3H), 3.88(s, 6H), 3.89(s, 3H), 3.93(s, 6H), 4.51 (s, 2H), 6.66(d, 2H, J=8.6Hz), 6.70(s, 2H), 6.75(s, 2H), 7.23 (d, 1H, J=7.0Hz), 7.32(dd, 1H,
# J=7.6Hz, 7.6Hz), 7.37(d, 1H, J=7.8Hz), 7.41(s, 1H), 7.77(s, 1H), 8.49(s, 1H), 8.69(s, 1H).
126
Figure US06867221-20050315-C00295
 		84% 1.71-1.88(m, 4H), 2.08-2.18(m, 2H), 2.21(s, 3H), 2.96-3.04(m, 2H), 3.58(s, 2H), 3.71-3.83(m, 1H), 3.87(s, 3H), 3.88(s, 6H), 3.89(s, 3H), 3.92(s, 6H), 4.52 (s, 2H), 6.66(d, 2H, J=8.6Hz), 6.70(s, 2H), 6.76(s, 2H), 6.98 (d, 2H, J=8.3Hz), 7.22-7.47(m,
# 8H).
PREPARATION EXAMPLE 153 Synthesis of 1-(tert-butoxycarbonyl)-4-[[4-(trifluoromethyl)phenyl]amino]piperidine
Figure US06867221-20050315-C00296
1-(tert-Butoxycarbonyl)-4-piperidone (5.00 g) and 4-(trifluoromethyl)aniline (3.85 g) was treated in the same manner as described in Preparation Example 37 to give white powder of the title compound.
Yield: 3.30 g (40%). 1H-NMR (400 MHz, CDCl3) δ: 1.30-1.41 (m, 2H), 1.47 (s, 9H), 2.00-2.07 (m, 2H), 2.88-2.99 (m, 2H), 3.32-3.52 (m, 1H), 3.83-3.89 (m, 1H), 4.00-4.14 (m, 2H), 6.59 (d, 2H, J=8.4 Hz), 7.39 (d, 2H, J=8.4 Hz).
PREPARATION EXAMPLE 154 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[4-(trifluoromethyl)phenyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00297
1-(tert-Butoxycarbonyl)-4-[[4-(trifluoromethyl)phenyl]amino]piperidine (688 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 412 mg (34%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.54-1.68 (m, 2H), 1.81-1.90 (m, 2H), 2.77-2.90 (m, 2H), 3.89 (s, 3H), 3.92 (s, 6H), 3.98-4.07 (m, 1H), 4.18-4.33(m, 2H), 4.55 (s, 2H), 6.73 (d, 2H, J=8.8 Hz), 7.09 (d, 1H, J=3.7 Hz), 7.13 (s, 2H), 7.44 (d, 2H, J=8.8 Hz), 7.49 (s, 1H), 8.58 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 155 Synthesis of 4-[N-[4-(trifluoromethyl)phenyl]-N-[[2-(3,4,5-trimethoxyphenyl) pyridin-4-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00298
1-(tert-Butoxycarbonyl)-4-[N-[4-(trifluoromethyl)phenyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine (412 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 359 mg (91%).
PREPARATION EXAMPLE 156 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[4-(trifluoromethyl)phenyl]-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine
Figure US06867221-20050315-C00299
1-(tert-Butoxycarbonyl)-4-[[4-(trifluoromethyl)phenyl]amino]piperidine (689 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 522 mg (44%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.58-1.70 (m, 2H), 1.83-1.90 (m, 2H), 2.76-2.87 (m, 2H), 3.87 (s, 6H), 3.88 (s, 3H), 3.96-4.06 (m, 1H), 4.15-4.30 (m, 2H), 4.58 (s, 2H), 6.68 (s, 2H), 6.76 (d, 2H, J=8.8 Hz), 7.19 (s, 1H, J=7.4 Hz), 7.33-7.44 (m, 5H).
PREPARATION EXAMPLE 157 Synthesis of 4-[N-[4-(trifluoromethyl)phenyl]-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine hydrochloride
Figure US06867221-20050315-C00300
1-(tert-Butoxycarbonyl)-4-[N-[4-(trifluoromethyl)phenyl]-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (522 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 460 mg (99%).
EXAMPLES 127 TO 132
These compounds were obtained by the condensation of amines obtained in Preparation Examples 155 and 157 with chloride derivatives obtained in Preparation Examples 3, 42 and 48. Free bases obtained were then converted to the corresponding hydrochlorides. Yields and NMR data of their free bases are listed below.
Ex-
am- NMR data (400 MHz, measured as
ple Structure Yield free bases, CDCl3) δ
127
Figure US06867221-20050315-C00301
 		72% 1.74-1.92(m, 4H), 2.17-2.26(m, 2H), 2.96-3.04(m, 2H), 3.59(s, 2H), 3.89(s, 3H), 3.90(s, 3H), 3.91(s, 6H), 3.96(s, 6H), 4.60(s, 2H), 6.72(d, 2H, J=8.8Hz), 7.10 (d, 1H, J=4.9Hz), 7.13(s, 2H), 7.20(d, 1H, J=5.1Hz), 7.43(d, 2H, J=8.8Hz), 7.50(s, 1H), 7.59
# (s, 1H), 8.56(d, 1H, J=4.9Hz), 8.58(d, 1H, J=5.1Hz).
128
Figure US06867221-20050315-C00302
 		51% 1.70-1.90(m, 4H), 2.14-2.28(m, 2H), 2.96-3.08(m, 2H), 3.61(s 2H), 3.87-3.96(m, 1H), 3.89(s, 3H), 3.90(s, 3H), 3.91(s, 6H), 3.93(s, 6H), 4.59(s, 2H), 6.71(d, 2H, J=8.8Hz), 6.75(s, 2H), 7.07- 7.15(m, 3H), 7.43(d, 2H, J=8.8 Hz), 7.49(s, 1H), 7.76(s, 1H),
# 8.51(d, 1H, J=1.8Hz), 8.57(d, 1H, J=5.1Hz), 8.70(s, 1H).
129
Figure US06867221-20050315-C00303
 		59% 1.72-1.88(m, 4H), 2.11-2.24(m, 2H), 2.98-3.10(m, 2H), 3.59(s, 2H), 3.87-3.95(m, 1H), 3.88(s, 3H), 3.89(s, 3H), 3.90(s, 6H), 3.92(s, 6H), 4.59(s, 2H), 6.71(d, 2H, J=9.0Hz), 6.76(s, 2H), 7.08 (d, 1H, J=5.1Hz), 7.12(s, 2H), 7.29(d, 1H, J=7.4Hz), 7.37(dd,
# 1H, J=7.6Hz, 7.6Hz), 7.40-7.52 (m, 5H), 8.56(d, 1H, J=5.1Hz).
130
Figure US06867221-20050315-C00304
 		81% 1.78-1.94(m, 4H), 2.15-2.27(m, 2H), 2.94-3.08(m, 2H), 3.58(s, 2H), 3.86(s, 6H), 3.87(s, 3H), 3.90(s, 3H), 3.96(s, 6H), 4.63(s, 2H), 6.67(s, 2H), 6.74(d, 2H, J=8.8Hz), 7.17-7.24(m, 4H), 7.34-7.45(m, 5H), 7.59(s, 1H), 8.59(d, 1H, J=5.1Hz).
131
Figure US06867221-20050315-C00305
 		54% 1.75-1.90(m, 4H), 2.14-2.24(m, 2H), 2.95-3.04(m, 2H), 3.60(s, 2H), 3.84-3.88(m, 1H), 3.86(m, 1H), 3.87(s, 3H), 3.90(s, 3H), 3.93(s, 6H), 4.61(s, 2H), 6.67(s, 2H), 6.72-6.77(m, 4H), 7.18(d, 1H, J=7.4Hz), 7.33-7.43(m, 5H), 7.76(s, 1H), 8.50(d, 1H, J=1.9
# Hz), 8.69(d, 1H, J=1.9Hz).
132
Figure US06867221-20050315-C00306
 		67% 1.76-1.88(m, 4H), 2.11-2.19(m, 2H), 2.98-3.06(m, 2H), 3.59(s, 2H), 3.86(s, 6H), 3.87(s, 3H), 3.89(s, 3H), 3.92(s, 6H), 4.61(s, 2H), 6.67(s, 2H), 6.73(d, 2H, J=8.8Hz), 6.76(s, 2H), 7.18(d, 1H, J=7.3Hz), 7.29(d, 1H, J=7.6 Hz), 7.32-7.47(m, 8H).
PREPARATION EXAMPLE 158 Synthesis of 4-(4-bromophenyl)amino-1-(tert-butoxycarbonyl)piperidine
Figure US06867221-20050315-C00307
1-(tert-Butoxycarbonyl)-4-piperidone (5.00 g) and 4-bromoaniline (4.11 g) was treated in the same manner as described in Example 37 to give white crystalline powder of the title compound.
Yield: 3.09 g (36%). 1H-NMR (400 MHz, CDCl3) δ: 1.25-1.37 (m, 2H), 1.46 (s, 9H), 1.97-2.05 (m, 2H), 2.86-2.96 (m, 2H), 3.33-3.42 (m, 2H), 3.47-3.57 (m, 1H), 3.96-4.12 (m, 2H), 6.47 (d, 2H, J=8.8 Hz), 7.24 (d, 2H, J=9.0 Hz).
PREPARATION EXAMPLE 159 Synthesis of 4-[N-(4-bromophenyl)-N-[[2-(3,4,5-trimethoxyphenyl) pyridin-4-yl]methyl]amino]-1-(tert-butoxycarbonyl)piperidine
Figure US06867221-20050315-C00308
4-(4-Bromophenyl)amino-1-(tert-butoxycarbonyl)piperidine (711 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 607 mg (50%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.50-1.64 (m, 2H), 1.81-1.88 (m, 2H), 2.74-2.88 (m, 2H), 3.86-3.94 (m, 1H), 3.89 (s, 3H), 3.93 (s, 6H), 4.14-4.32 (m, 2H), 4.46 (s, 2H), 6.59 (d, 2H, J=9.1 Hz), 7.10 (d, 1H, J=5.2 Hz), 7.14 (s, 2H), 7.28 (d, 2H, J=9.1 Hz), 7.50 (s, 1H), 8.57 (d, 1H, J=5.0 Hz).
PREPARATION EXAMPLE 160 Synthesis of 4-[N-(4-bromophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00309
4-[N-(4-Bromophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]-1-(tert-butoxycarbonyl)piperidine (607 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 541 mg (93%).
PREPARATION EXAMPLE 161 Synthesis of 4-[N-(4-bromophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]-1-(tert-butoxycarbonyl)piperidine
Figure US06867221-20050315-C00310
4-(4-Bromophenyl)amino-1-(tert-butoxycarbonyl)piperidine (711 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 347 mg (28%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.52-1.67 (m, 2H), 1.80-1.89 (m, 2H), 2.72-2.87 (m, 2H), 3.82-3.92 (m, 1H), 3.89 (s, 3H), 3.90 (s, 6H), 4.14-4.33 (m, 2H), 4.50 (s, 2H), 6.63 (d, 2H, J=9.2 Hz), 6.65 (s, 2H), 7.28 (d, 2H, J=9.4 Hz), 7.61 (s, 1H), 8.47 (d, 1H, J=2.0 Hz), 8.67 (d, 1H, J=2.2 Hz).
PREPARATION EXAMPLE 162 Synthesis of 4-[N-(4-bromophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00311
4-[N-(4-Bromophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]-1-(tert-butoxycarbonyl)piperidine (347 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 302 mg (91%).
PREPARATION EXAMPLE 163 Synthesis of 4-[N-(4-bromophenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-(tert-butoxycarbonyl)piperidine
Figure US06867221-20050315-C00312
4-(4-Bromophenyl)amino-1-(tert-butoxycarbonyl)piperidine (711 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 1.14 g (93%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.52-1.67 (m, 2H), 1.80-1.89 (m, 2H), 2.72-2.86 (m, 2H), 3.84-3.91 (m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 4.11-4.32 (m, 2H), 4.49 (s, 2H), 6.62 (d, 2H, J=9.2 Hz), 6.69 (s, 2H), 7.19 (d, 1H, J=7.6 Hz), 7.25 (d, 2H, J=5.5 Hz), 7.32-7.42 (m, 3H).
PREPARATION EXAMPLE 164 Synthesis of 4-[N-(4-bromophenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine hydrochloride
Figure US06867221-20050315-C00313
4-[N-(4-Bromophenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-(tert-butoxycarbonyl)piperidine (1.14 g) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 973 mg (84%).
EXAMPLES 133 TO 140
These compounds were obtained by the condensation of amines obtained in Preparation Examples 160, 162 and 164 with chloride derivatives obtained in Preparation Examples 3, 42 and 48. Free bases obtained were then converted to the corresponding hydrochlorides. Yields and NMR data of their free bases are listed below.
Ex-
am- NMR data (400 MHz, measured as
ple Structure Yield free bases, CDCl3) δ
133
Figure US06867221-20050315-C00314
 		52% 1.70-1.90(m, 4H), 2.14-2.25(m, 2H), 2.94-3.04(m, 2H), 3.58(s, 2H), 3.73-3.84(m, 1H), 3.89(s, 3H), 3.90(s, 3H), 3.92(s, 6H), 3.96(s, 6H), 4.52(s, 2H), 6.57(d, 2H, J=8.8Hz), 7.10(d, 1H, J=4.9 Hz), 7.14(s, 2H), 7.20(d, 1H, J=4.9Hz), 7.22(s, 2H), 7.26(d,
# 2H, J=8.5Hz), 7.51(s, 1H), 7.59 (s, 1H), 8.56(d, 1H, J=4.9Hz), 8.59(d, 1H, J=4.9Hz).
134
Figure US06867221-20050315-C00315
 		56% 1.68-1.88(m, 4H), 2.12-2.24(m, 2H), 2.95-3.04(m, 2H), 3.59(s, 2H), 3.72-3.84(m, 1H), 3.89(s, 3H), 3.90(s, 3H), 3.92(s, 6H), 3.93(s, 6H), 4.50(s, 2H), 6.57(d, 2H, J=9.2Hz), 6.74(s, 2H), 7.09 (d, 1H, J=3.9Hz), 7.13(s, 2H), 7.26(d, 2H, J=8.8Hz), 7.50(s,
# 1H), 7.75(s, 1H), 8.50(d, 1H, J=2.0Hz), 8.55(d, 1H, J=5.0Hz), 8.69(d, 1H, J=2.0Hz).
135
Figure US06867221-20050315-C00316
 		65% 1.70-1.86(m, 4H), 2.10-2.20(m, 2H), 2.97-3.08(m, 2H), 3.59(s, 2H), 3.72-3.82(m, 1H), 3.89(s, 6H), 3.92(s, 6H), 3.92(s, 6H), 4.50(s, 2H), 6.56(d, 2H, J=9.2 Hz), 6.76(s, 2H), 7.09(d, 1H, J=5.1Hz), 7.13(s, 2H), 7.23-7.33 (m, 3H), 7.37(dd, 1H, J=7.4Hz),
# 7.41-7.48(m, 2H), 7.49(s, 1H), 8.54(d, 1H, J=5.1Hz).
136
Figure US06867221-20050315-C00317
 		49% 1.77-1.93(m, 4H), 2.12-2.30(m, 2H), 2.94-3.10(m, 2H), 3.60(s, 2H), 3.73-3.83(m, 1H), 3.88(s, 3H), 3.89(s, 6H), 3.90(s, 3H), 3.96(s, 6H), 4.55(s, 2H), 6.61(d, 2H, J=9.2Hz), 6.65(s, 2H), 7.19- 7.29(m, 5H), 7.62(br, 2H), 8.47 (d, 1H, J=1.6Hz), 8.60(d, 1H,
# J=4.9Hz), 8.66(d, 1H, J=2.0Hz).
137
Figure US06867221-20050315-C00318
 		50% 1.70-1.92(m, 4H), 2.12-2.27(m, 2H), 2.93-3.07(m, 2H), 3.60(s, 2H), 3.67-4.08(m, 1H), 3.88(s, 3H), 3.89(s, 6H), 3.90(s, 3H), 3.93(s, 6H), 4.54(s, 2H), 6.60(d, 2H, J=9.0Hz), 6.64(s, 2H), 6.73- 6.80(m, 2H), 7.25(s, 2H), 7.61(s, 1H), 7.77(br, 1H), 8.45(d, 1H,
# J=1.7Hz), 8.50(d, 1H, J=1.7Hz), 8.65(d, 1H, J=2.0Hz).
138
Figure US06867221-20050315-C00319
 		81% 1.75-1.90(m, 4H), 2.17-2.24(m, 2H), 2.94-3.02(m, 2H), 3.57(s, 2H), 3.72-3.83(m, 1H), 3.88(s, 3H), 3.88(s, 6H), 3.90(s, 3H), 3.95(s, 6H), 4.54(s, 2H), 6.60(d, 2H, J=9.2Hz), 6.69(s, 2H), 7.18- 7.27(m, 6H), 7.32-7.42(m, 3H), 7.60(s, 1H), 8.58(d, 1H, J=4.9
# Hz).
139
Figure US06867221-20050315-C00320
 		80% 1.72-1.90(m, 4H), 2.13-2.21(m, 2H), 2.94-3.05(m, 2H), 3.59(s, 2H), 3.72-3.82(m, 1H), 3.87(s, 3H), 3.88(s, 6H), 3.89(s, 3H), 3.93(s, 6H), 4.53(s, 2H), 6.60(d, 2H, J=9.0Hz), 6.68(s, 2H), 6.75 (s, 2H), 7.19(d, 1H, J=7.2Hz), 7.24(d, 2H, 1=9.0Hz), 7.31-7.41
# (m, 3H), 7.76(s, 1H), 8.50(d, 1H, J=1.8Hz), 8.70(s, 1H).
140
Figure US06867221-20050315-C00321
 		78% 1.72-1.88(m, 4H), 2.08-2.18(m, 2H), 2.97-3.06(m, 2H), 3.58(s, 2H), 3.71-3.82(m, 1H), 3.87(s, 3H), 3.88(s, 6H), 3.89(s, 3H), 3.92(s, 6H), 4.53(s, 2H), 6.59(d, 2H, J=9.3Hz), 6.68(s, 2H), 6.76 (s, 2H), 7.18(d, 1H, J=7.3Hz), 7.21-7.47(m, 9H)
PREPARATION EXAMPLE 165 Synthesis of 1-(tert-butoxycarbonyl)-4-[(4-chlorophenyl)amino]piperidine
Figure US06867221-20050315-C00322
1-(tert-Butoxycarbonyl)-4-piperidone (5.00 g) and 4-chloroaniline (3.05 g) was treated in the same manner as described in Preparation Example 37 to give white powder of the title compound.
Yield: 3.80 g (49%). 1H-NMR (400 MHz, CDCl3) δ: 1.24-1.38 (m, 2H), 1.46 (s, 9H), 1.97-2.05 (m, 2H), 2.86-2.96 (m, 2H), 3.32-3.42 (m, 2H), 3.51 (br, 1H), 6.52 (d, 2H, J=9.0 Hz), 7.11 (d, 2H, J=9.0 Hz).
PREPARATION EXAMPLE 166 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-chlorophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00323
1-(tert-Butoxycarbonyl)-4-[(4-chlorophenyl)amino]piperidine (621 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 789 mg (69%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.51-1.68 (m, 2H), 1.80-1.89 (m, 2H), 2.72-2.86 (m, 2H), 3.87-3.90 (m, 1H), 3.89 (s, 3H), 3.93 (s, 6H), 4.64 (s, 2H), 6.64 (d, 2H, J=9.0 Hz), 7.14 (d, 1H, J=5.3 Hz), 7.15 (d, 2H, J=9.0 Hz), 7.51 (s, 2H), 8.57 (d, 2H, J=5.1 Hz).
PREPARATION EXAMPLE 167 Synthesis of 4-[N-(4-chlorophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00324
1-(tert-Butoxycarbonyl)-4-[N-(4-chlorophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine 789 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 673 mg (90%).
PREPARATION EXAMPLE 168 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-chlorophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00325
1-(tert-Butoxycarbonyl)-4-[(4-chlorophenyl)amino]piperidine (621 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 268 mg (24%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.56-1.76 (m, 2H), 1.80-1.90 (m, 2H), 2.76-2.83 (m, 2H), 3.86-3.90 (m, 1H), 3.89 (s, 3H), 3.90 (s, 6H), 4.15-4.30 (m, 2H), 4.50 (s, 2H), 6.66 (s, 2H), 6.68 (d, 2H, J=9.2 Hz), 7.15 (d, 2H, J=9.0 Hz), 7.63 (s, 1H), 8.47 (d, 1H, J=2.0 Hz), 8.66 (d, 1H, J=2.0 Hz).
PREPARATION EXAMPLE 169 Synthesis of 4-[N-(4-chlorophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00326
1-(tert-Butoxycarbonyl)-4-[N-(4-chlorophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine (268 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 233 mg (91%).
PREPARATION EXAMPLE 170 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-chlorophenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine
Figure US06867221-20050315-C00327
1-(tert-Butoxycarbonyl)-4-[4-(chlorophenyl)amino]piperidine (622 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 1.04 g (92%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.58-1.67 (m, 2H), 1.82-1.91 (m, 2H), 2.74-2.86 (m, 2H), 3.85-3.92 (m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 4.35-4.31 (m, 2H), 4.49 (s, 2H), 6.66 (d, 2H, J=9.2 Hz), 6.70 (s, 2H), 7.12 (d, 2H, J=9.0 Hz), 7.20 (d, 2H, J=7.3 Hz), 7.33-7.43 (m, 3H).
PREPARATION EXAMPLE 171 Synthesis of 4-[N-(4-chlorophenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine hydrochloride
Figure US06867221-20050315-C00328
1-(tert-Butoxycarbonyl)-4-[N-(4-chlorophenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (1.04 g) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 899 mg (97%).
EXAMPLES 141 TO 148
These compounds were obtained by the condensation of amines obtained in Preparation Examples 167, 169 and 171 with chloride derivatives obtained in Preparation Examples 3, 42 and 48. Free bases obtained were then converted to the corresponding hydrochlorides. Yields and NMR data of their free bases are listed below.
Ex-
am- NMR data (400 MHz, measured as
ple Structure Yield free bases, CDCl3) δ
141
Figure US06867221-20050315-C00329
 		66% 1.71-1.90(m, 4H), 2.15-2.24(m, 2H), 2.95-3.05(m, 2H), 3.58(s, 2H), 3.73-3.84(m, 1H), 3.89(s, 3H), 3.90(s, 3H), 3.93(s, 6H), 3.96(s, 6H), 4.52(s, 2H), 6.62(d, 2H, J=9.0Hz), 7.10-7.16(m, 5H), 7.19-7.24(m, 3H), 7.52(s, 1H), 7.59(s, 1H), 8.56(d, 1H, J=4.9
# Hz), 8.59(d, 1H, J=4.9Hz).
142
Figure US06867221-20050315-C00330
 		67% 1.69-1.90(m, 1H), 2.12-2.25(m, 2H), 2.93-3.06(m, 2H), 3.59(s, 2H), 3.72-3.83(m, 1H), 3.89(s, 3H), 3.90(s, 3H), 3.92(s, 6H), 3.93(s, 6H), 4.50(s, 2H), 6.62(d, 2H, J=9.2Hz), 6.75(s, 2H), 7.10 (d, 1H, J=5.3Hz), 7.13(s, 2H), 7.13(d, 2H, J=9.0Hz), 7.50(s,
# 1H), 7.76(s, 1H), 8.50(d, 1H, J=1.8Hz), 8.55(d, 1H, J=5.1Hz), 8.70(d, 1H, J=1.8Hz).
143
Figure US06867221-20050315-C00331
 		70% 1.65-1.88(m, 4H), 2.08-2.20(m, 2H), 2.97-3.07(m, 2H), 3.59(s, 2H), 3.71-3.82(m, 1H), 3.88(s, 3H), 3.89(s, 3H), 3.90-3.93(m, 3H), 4.50(s, 2H), 6.61(d, 2H, J=8.2Hz), 6.76(s, 2H), 7.07-7.14 (m, 5H), 7.28(d, 1H, J=6.6Hz), 7.37(dd, 1H, J=7.4Hz), 7.40-7.47
# (m, 2H), 7.50(s, 1H), 8.54(d, 1H, J=5.1Hz).
144
Figure US06867221-20050315-C00332
 		57% 1.56-1.93(m, 4H), 2.12-2.30(m, 2H), 2.92-3.10(m, 2H), 3.53-3.68 (m, 2H), 3.70-3.82(m, 1H), 3.88 (s, 3H), 3.89(s, 6H), 3.90(s, 3H), 3.96(s, 6H), 4.56(s, 2H), 6.64- 6.70(m, 4H), 7.13(d, 2H, J=9.0 Hz), 7.20-7.30(m, 3H), 7.63(br, 2H), 8.48(s, 1H), 8.60(d, 1H,
# J=5.1Hz), 8.66(d, 1H, J=2.2Hz).
145
Figure US06867221-20050315-C00333
 		70% 1.71-1.92(m, 4H), 2.12-2.27(m, 2H), 2.94-3.07(m, 2H), 3.59(s, 2H), 3.69-3.81(s, 1H), 3.88(s, 3H), 3.89(s, 6H), 3.90(s, 3H), 3.93(s, 6H), 4.54(s, 2H), 6.63- 6.68(m, 4H), 6.75(s, 2H), 7.13(d, 2H, J=9.0Hz), 7.62(s, 1H), 7.76 (s, 1H), 8.47(d, 1H, J=1.8Hz),
# 8.50(d, 1H, J=1.8Hz), 8.65(d, 1H, J=2.0Hz), 8.70(s, 1H).
146
Figure US06867221-20050315-C00334
 		78% 1.75-1.91(m, 4H), 2.13-2.23(m, 2H), 2.94-3.02(m, 2H), 3.57(s, 2H), 3.73-3.82(m, 1H), 3.88(s, 3H), 3.88(s, 6H), 3.90(s, 3H), 3.96(s, 6H), 4.55(s, 2H), 6.65(d, 2H, J=9.0Hz), 6.68(s, 2H), 7.11 (d, 2H, J=8.5Hz), 7.18-7.24(m, 4H), 7.32-7.42(m, 3H), 7.59(s,
# 1H), 8.59(d, 1H, J=4.9Hz).
147
Figure US06867221-20050315-C00335
 		63% 1.72-1.89(m, 4H), 2.12-2.21(m, 2H), 2.94-3.03(m, 2H), 3.59(s, 2H), 3.72-3.82(m, 1H), 3.87(s, 3H), 3.88(s, 6H), 3.90(s, 3H), 3.93(s, 6H), 4.53(s, 2H), 6.64(d, 2H, J=9.2Hz), 6.68(s, 2H), 6.75 (s, 2H), 7.11(d, 2H), 7.19(d, 1H, J=7.6Hz), 7.32-7.40(m, 3H), 7.76
# (s, 1H), 8.50(d, 1H, J=1.8Hz), 8.69(d, 1H, J=2.2Hz).
148
Figure US06867221-20050315-C00336
 		68% 1.72-1.87(m, 4H), 2.08-2.18(m, 2H), 2.97-3.05(m, 2H), 3.58(s, 2H), 3.71-3.82(m, 1H), 3.87(s, 3H), 3.88(s, 6H), 3.89(s, 3H), 3.92(s, 6H), 4.53(s, 2H), 6.64(dt, 2H, J=9.3Hz, 2.9Hz), 6.68(s, 2H), 6.76(s, 2H), 7.10(dt, 2H, J=9.0Hz, 2.8Hz), 7.19(d, 1H,
# J=7.6Hz), 7.24-7.47(m, 7H).
PREPARATION EXAMPLE 172 Synthesis of 1-(tert-butoxycarbonyl)-4-[(3,4-difluorophenyl)amino]piperidine
Figure US06867221-20050315-C00337
1-(tert-Butoxycarbonyl)-4-piperidone (5.00 g) and 3,4-difluoroaniline (3.09 g) was treated in the same manner as described in Preparation Example 37 to give light brown prism crystal of the title compound.
Yield: 4.66 g (62%). 1H-NMR (400 MHz, CDCl3) δ: 1.24-1.37 (m, 2H), 1.46 (s, 9H), 1.97-2.05 (m, 2H), 2.85-2.96 (m, 2H), 3.26-3.36 (m, 1H), 3.38-3.52 (m, 1H), 3.96-4.14 (m, 2H), 6.22-6.28 (m, 1H), 6.38 (ddd, 1H, J=12.7 Hz, 6.6 Hz, 2.9 Hz), 6.94 (dd, 1H, J=19.1 Hz, 9.0 Hz).
PREPARATION EXAMPLE 173 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(3,4-difluorophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00338
1-(tert-Butoxycarbonyl)-4-[(3,4-difluorophenyl)amino]piperidine (625 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 534 mg (47%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.50-1.70 (m, 2H), 1.82-1.90 (m, 2H), 2.73-2.88 (m, 2H), 3.90 (s, 3H), 3.94 (s, 6H), 4.15-4.30 (m, 2H), 4.43 (s, 2H), 6.33-6.39 (m, 1H), 6.52 (ddd, 1H, J=13.6 Hz, 6.4 Hz, 3.1 Hz), 6.98 (dd, 1H, J=19.1 Hz, 9.2 Hz). 7.11 (dd, 1H, J=5.0 Hz, 1.3 Hz), 7.16 (s, 2H), 7.51 (s, 1H), 8.58 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 174 Synthesis of 4-[N-(3,4-difluorophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00339
1-(tert-Butoxycarbonyl)-4-[N-(3,4-difluorophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine (534 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 442 mg (87%).
PREPARATION EXAMPLE 175 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(3,4-difluorophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00340
1-(tert-Butoxycarbonyl)-4-[(3,4-difluorophenyl)amino]piperidine (625 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 350 mg (31%).
PREPARATION EXAMPLE 176 Synthesis of 4-[N-(3,4-difluorophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00341
1-(tert-Butoxycarbonyl)-4-[N-(3,4-difluorophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine (350 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 305 mg (92%).
PREPARATION EXAMPLE 177 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(3,4-difluorophenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine
Figure US06867221-20050315-C00342
1-(tert-Butoxycarbonyl)-4-[(3,4-difluorophenyl)amino]piperidine (625 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 980 mg (86%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.52-1.66 (m, 2H), 1.81-1.89 (m, 2H), 2.72-2.85 (m, 2H), 3.78 (tt, 1H, J=11.8 Hz, 3.8 Hz), 3.88 (s, 3H), 3.90 (s, 6H), 4.12-4.30 (m, 2H), 4.45 (s, 2H), 6.36-6.42 (m, 1H), 6.54 (ddd, 1H, J=13.9 Hz, 6.8 Hz, 2.9 Hz), 6.71 (s, 2H), 6.95 (dd, 1H, J=19.2 Hz, 9.2 Hz), 7.20 (d, 1H, J=7.4 Hz), 7.36-7.43 (m, 3H).
PREPARATION EXAMPLE 178 Synthesis of 4-[N-(3,4-difluorophenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine hydrochloride
Figure US06867221-20050315-C00343
1-(tert-Butoxycarbonyl)-4-[N-(3,4-difluorophenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (980 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 819 mg (94%).
EXAMPLES 149 TO 156
These compounds were obtained by the condensation of amines obtained in Preparation Examples 174, 176 and 178 with chloride derivatives obtained in Preparation Examples 3, 42 and 48. Free bases obtained were then converted to the corresponding hydrochlorides. Yields and NMR data of their free bases are listed below.
Ex-
am- NMR data(400 MHz, measured as
ple Structure Yield free bases, CDCl3) δ
149
Figure US06867221-20050315-C00344
 		67% 1.70-1.90(m, 4H), 2.16-2.23(m, 2H), 2.95-3.03(m, 2H), 3.58(s, 2H), 3.64-3.74(m, 1H), 3.89(s, 3H), 3.90(s, 3H), 3.93(s, 6H), 3.96(s, 6H), 4.49(s, 2H), 6.31- 6.37(m, 1H), 6.51(ddd, 1H, J=13.9Hz, 6.6Hz, 3.1Hz), 6.96 (dd, 1H, J=19.2Hz, 9.8Hz), 7.11
# (d, 1H, J=5.1Hz), 7.15(s, 2H), 7.20(d, 1H, J=5.1Hz), 7.22(s, 2H), 7.52(s, 1H), 7.59(s, 1H), 8.57(d, 1H, J=5.1Hz), 8.59(d, 1H, J=5.1Hz).
150
Figure US06867221-20050315-C00345
 		47% 1.67-1.79(m, 2H), 1.81-1.89(m, 2H), 2.13-2.20(m, 2H), 2.95-3.05 (m, 2H), 3.59(s, 2H), 3.63-3.75 (m, 1H), 3.89(s, 3H), 3.90(s, 3H), 3.93(s, 12H), 4.47(s, 2H), 6.30- 6.36(m, 1H), 6.50(ddd, 1H, J=13.9Hz, 6.6Hz, 3.1Hz), 6.75(s, 2H), 6.96(d, 1H, J=19.0Hz, 9.4
# Hz), 7.10(d, 1H, J=4.1Hz), 7.15 (s, 2H), 7.51(s, 1H), 7.75(s, 1H), 8.50(d, 1H, J=1.8Hz), 8.56(d, 1H, J=5.1Hz), 8.70(s, 1H).
151
Figure US06867221-20050315-C00346
 		53% 1.68-1.87(m, 4H), 2.09-2.18(m, 2H), 2.98-3.06(m, 2H), 3.58(s, 2H), 3.63-3.72(m, 1H), 3.89(s, 3H), 3.89(s, 3H), 3.92(s, 6H), 3.93(s, 6H), 4.47(s, 2H), 6.33- 6.35(m, 1H), 6.50(ddd, 1H, J=13.9Hz, 6.4Hz, 2.9Hz), 6.76(s, 2H), 6.95(dd, 1H, J=19.2Hz, 9.4
# Hz), 7.09(d, 1H, J=5.1Hz), 7.15 (s, 2H), 7.25-7.30(m, 1H), 7.37 (dd, 1H, J=7.3Hz, 7.3Hz), 7.42- 7.46(m, 2H), 7.50(s, 1H), 8.56(d, 1H, J=5.1Hz).
152
Figure US06867221-20050315-C00347
 		50% 1.72-1.96(m, 4H), 2.12-2.28(m, 2H), 2.94-3.08(m, 2H), 3.59(s, 2H), 3.62-3.72(m, 1H), 3.89(s, 3H), 3.90(s, 9H), 3.96(s, 6H), 4.52(s, 2H), 6.36-6.43(m, 1H), 6.55(ddd, 1H, J=13.7Hz, 6.6Hz, 2.9Hz), 6.67(s, 2H), 6.96(dd, 1H, J=19.1Hz, 9.2Hz), 7.21(dd, 1H,
# J=5.1Hz, 1.2Hz), 7.24(s, 2H), 7.61(br, 1H), 7.64(s, 1H), 8.47(d, 1H, J=2.0Hz), 8.60(d, 1H, J=4.9 Hz), 8.67(d, 1H, J=2.0Hz).
153
Figure US06867221-20050315-C00348
 		61% 1.71-1.90(m, 4H), 2.12-2.25(m, 2H), 2.95-3.05(m, 2H), 3.57-3.75 (m, 1H), 3.59(s, 2H), 3.88(s, 3H), 3.90(s, 9H), 3.93(s, 6H), 4.50(s, 2H), 6.32-6.43(m, 1H), 6.54(ddd, 1H, J=13.6Hz, 6.4Hz, 2.7Hz), 6.67(s, 2H), 6.73-6.78(m, 3H), 6.96(dd, 1H, J=18.9Hz, 9.6Hz), 7.63(s, 1H), 7.76(s, 1H), 8.46(s,
# 1H), 8.50(d, 1H, J=1.6Hz), 8.66 (d, 1H, J=1.8Hz), 8.70(d, 1H, J=2.0Hz).
154
Figure US06867221-20050315-C00349
 		82% 1.74-1.90(m, 4H), 2.13-2.22(m, 2H), 2.95-3.01(m, 2H), 3.57(s, 2H), 3.63-3.73(m, 1H), 3.88(s, 3H), 3.89(s, 6H), 3.90(s, 3H), 3.96(s, 6H), 4.51(s, 2H), 6.34- 6.40(m, 1H), 6.52(ddd, 1H, J=14.1Hz, 6.6Hz, 3.1Hz), 6.70(s, 2H), 6.94(dd, 1H, J=19.2Hz, 9.4
# Hz), 7.17-7.26(m, 4H), 7.32-7.42 (m, 3H), 7.59(s, 1H), 8.59(d, 1H, J=5.1Hz).
155
Figure US06867221-20050315-C00350
 		75% 1.74-1.90(m, 4H), 2.13-2.21(m, 2H), 2.95-3.04(m, 2H), 3.59(s, 2H), 3.63-3.72(m, 1H), 3.88(s, 3H), 3.89(s, 6H), 3.89(s, 3H), 3.93(s, 6H), 4.49(s, 2H), 6.33- 6.39(m, 1H), 6.52(ddd, 1H, J=14.3Hz, 3.7Hz, 2.9Hz), 6.69(s, 2H), 6.75(s, 2H), 6.94(dd, 1H,
# J=19.1Hz, 9.8Hz), 7.19(d, 1H, J=7.8Hz), 7.32-7.41(m, 3H), 7.76 (s, 1H), 8.50(d, 1H, J=1.5Hz), 8.69(s, 1H).
156
Figure US06867221-20050315-C00351
 		79% 1.72-1.88(m, 4H), 2.08-2.18(m, 2H), 2.98-3.05(m, 2H), 3.58(s, 2H), 3.62-3.72(m, 1H), 3.88(s, 3H), 3.89(s, 9H), 3.92(s, 6H), 4.45(s, 2H), 6.33-6.39(m, 1H), 6.51(ddd, 1H, J=13.9Hz, 6.6Hz, 3.0Hz), 6.69(s, 2H), 6.76(s, 2H), 6.93(dd, 1H, J=19.3Hz, 9.5Hz),
# 7.19(d, 1H, J=7.6Hz), 7.25-7.47 (m, 7H).
PREPARATION EXAMPLE 179 Synthesis of 1-(tert-butoxycarbonyl)-4-[(4-fluorophenyl)amino]piperidine
Figure US06867221-20050315-C00352
1-(tert-Butoxycarbonyl)-4-piperidone (5.00 g) and 4-fluoroaniline (2.66 g) was treated in the same manner as described in Preparation Example 37 to give white crystalline powder of the title compound.
Yield: 4.99 g (71%). 1H-NMR (400 MHz, CDCl3) δ: 1.23-1.36 (m, 2H), 1.46 (s, 9H), 1.97-2.05 (m, 2H), 2.84-2.96 (m, 2H), 3.30-3.39 (m, 2H), 3.96-4.14 (m, 2H), 6.51-6.57 (m, 2H), 6.84-6.91 (m, 2H).
PREPARATION EXAMPLE 180 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-fluorophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00353
1-(tert-Butoxycarbonyl)-4-[(4-fluorophenyl)amino]piperidine (589 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 702 mg (64%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.48-1.64 (m, 2H), 1.81-1.90 (m, 2H), 2.72-2.85 (m, 2H), 3.69-3.98 (m, 1H), 3.89 (m, 3H), 3.94 (m, 6H), 4.16-4.28 (m, 2H), 4.43 (s, 2H), 6.66-6.73 (m, 2H), 6.91 (dd, 2H, J=9.2 Hz, 9.2 Hz), 7.12-7.16 (m, 3H), 7.53 (s, 1H).
PREPARATION EXAMPLE 181 Synthesis of 4-[N-(4-fluorophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00354
1-(tert-Butoxycarbonyl)-4-[N-(4-fluorophenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine (702 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 561 mg (84%).
PREPARATION EXAMPLE 182 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-fluorophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00355
1-(tert-Butoxycarbonyl)-4-[(4-fluorophenyl)amino]piperidine (589 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 190 mg (17%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.50-1.73 (m, 2H), 1.82-1.90 (m, 2H), 2.71-2.85 (m, 2H), 3.71 (tt, 1H, J=11.7 Hz, 3.1 Hz), 3.89 (s, 3H), 3.90 (s, 6H), 4.12-4.30 (m, 2H), 4.45 (s, 2H), 6.66 (s, 2H), 6.73-6.78 (m, 2H), 6.91 (dd, 2H, J=9.2 Hz, 8.2 Hz), 7.65 (s, 1H), 8.49 (d, 1H, J=2.0 Hz), 8.65 (d, 1H, J=2.0 Hz).
PREPARATION EXAMPLE 183 Synthesis of 4-[N-(4-fluorophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00356
1-(tert-Butoxycarbonyl)-4-[N-(4-fluorophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine (190 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 165 mg (91%).
PREPARATION EXAMPLE 184 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-fluorophenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine
Figure US06867221-20050315-C00357
1-(tert-Butoxycarbonyl)-4-[(4-fluorophenyl)amino]piperidine (589 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 1.01 g (92%). 1H-NMR (400 MHz, CDCl3) δ: 1.44 (s, 9H), 1.51-1.65 (m, 2H), 1.82-1.90 (m, 2H), 2.82-2.84 (m, 2H), 3.78 (tt, 1H, J=11.7 Hz, 3.5 Hz), 3.88 (s, 3H), 3.90 (s, 6H), 4.10-4.30 (m, 2H), 4.45 (s, 2H), 6.68-6.73 (m, 4H), 6.89 (dd, 2H, J=9.2 Hz, 8.2 Hz), 7.21-7.25 (m, 1H, 7.32-7.41 (m, 3H).
PREPARATION EXAMPLE 185 Synthesis of 4-[N-(4-fluorophenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine hydrochloride
Figure US06867221-20050315-C00358
1-(tert-Butoxycarbonyl)-4-[N-(4-fluorophenyl)-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (1.01 g) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 790 mg (88%).
EXAMPLES 157 TO 164
These compounds were obtained by the condensation of amines obtained in Preparation Examples 181, 183 and 185 with chloride derivatives obtained in Preparation Examples 3, 42 and 48. Free bases obtained were then converted to the corresponding hydrochlorides. Yields and NMR data of their free bases are listed below.
Ex-
am- NMR data (400 MHz, measured as
ple Structure Yield free bases, CDCl3) δ
157
Figure US06867221-20050315-C00359
 		62% 1.60-1.82(m, 2H), 1.83-1.91(m, 2H), 2.13-2.23(m, 2H), 2.95-3.03 (m, 2H), 3.57(s, 2H), 3.64-3.75 (m, 1H), 3.89(s, 3H), 3.90(s, 3H), 3.93(s, 6H), 3.96(s, 6H), 4.48(s, 2H), 6.65-6.70(m, 2H), 6.90(dd, 2H, J=8.8Hz, 8.8Hz), 7.13-7.16 (m, 3H), 7.20(d, 1H, J=5.1Hz),
# 7.22(s, 2H), 7.54(s, 1H), 7.59(s, 1H), 8.55(d, 1H, J=5.1Hz), 8.59 (d, 1H, J=4.9Hz).
158
Figure US06867221-20050315-C00360
 		53% 1.66-1.95(m, 4H), 2.12-2.24(m, 2H), 2.95-3.07(m, 2H), 3.60(s, 2H), 3.64-3.76(m, 1H), 3.89(s, 3H), 3.90(s, 3H), 3.92(s, 6H), 3.93(s, 6H), 4.47(s, 2H), 6.63- 6.70(m, 1H), 6.75(s, 2H), 6.90 (dd, 1H, J=9.2Hz, 9.2Hz), 7.11- 7.16(m, 3H), 7.53(s, 1H), 7.77(s,
# 1H), 8.50(d, 1H, J=2.0Hz), 8.55 (d, 1H, J=4.9Hz), 8.70(d, 1H, J=5.9Hz).
159
Figure US06867221-20050315-C00361
 		51% 1.64-1.90(m, 4H), 2.07-2.20(m, 4H), 2.97-3.08(m, 2H), 3.59(s, 2H), 3.64-3.76(m, 1H), 3.89(s, 6H), 3.92(s, 6H), 3.93(s, 6H), 4.47(s, 2H), 6.62-6.70(m, 2H), 6.77(s, 2H), 6.86-6.93(m, 2H), 7.11-7.16(m, 3H), 7.25-7.31(m, 3H), 7.37(dd, 1H, J=7.4Hz, 7.4 Hz), 7.42-7.49(m, 2H), 7.53(s,
# 1H), 8.54(d, 1H, J=5.1Hz).
160
Figure US06867221-20050315-C00362
 		49% 1.74-1.98(m, 4H), 2.10-2.30(m, 2H), 2.90-3.12(m, 2H), 3.53-3.73 (m, 3H), 3.88(s, 3H), 3.89(s, 6H), 3.90(s, 3H), 3.96(s, 6H), 4.50(s, 2H), 6.66(s, 2H), 6.70-6.76(m, 2H), 6.90(dd, 2H, J=8.8Hz, 8.8 Hz), 7.19-7.28(m, 3H), 7.65(br, 2H), 8.49(d, 1H, J=1.8Hz), 8.60
# (d, 1H, J=4.9Hz), 8.64(d, 1H, J=2.2Hz).
161
Figure US06867221-20050315-C00363
 		26% 1.67-1.97(m, 4H), 2.10-2.27(m, 2H), 2.94-3.06(m, 2H), 3.56-3.68 (m, 3H), 3.88(s, 3H), 3.89(s, 6H), 3.90(s, 3H), 3.93(s, 6H), 4.49(s, 2H), 6.65(s, 2H), 6.69-6.80(m, 4H), 6.84-6.93(m, 2H), 7.64(s, 1H), 7.77(br, 1H), 8.48(d, 1H, J=1.7Hz), 8.50(d, 1H, J=1.7Hz),
# 8.64(d, 1H, J=1.9Hz), 8.70(s, 1H).
162
Figure US06867221-20050315-C00364
 		83% 1.72-1.92(m, 4H), 2.12-2.21(m, 2H), 2.94-3.02(m, 2H), 3.57(s, 2H), 3.64-3.74(m, 1H), 3.88(s, 3H), 3.89(s, 6H), 3.90(s, 3H), 3.96(s, 6H), 4.51(s, 1H), 6.66- 6.71(m, 4H), 6.88(dd, 2H, J=8.6 Hz, 8.6Hz), 7.18-7.27(m, 4H), 7.34(dd, 1H, J=7.4Hz, 7.4Hz),
# 7.39(d, 2H, J=5.4Hz), 7.59(s, 1H), 8.59(d, 1H, J=5.1Hz).
163
Figure US06867221-20050315-C00365
 		68% 1.68-1.87(m, 4H), 2.10-2.22(m, 2H), 2.94-3.04(m, 2H), 3.59(s, 2H), 3.65-3.74(m, 1H), 3.87(s, 3H), 3.88(s, 6H), 3.90(s, 3H), 3.93(s, 6H), 4.49(s, 2H), 6.66- 6.70(m, 6H), 6.88(dd, 2H, J=8.8 Hz, 8.8Hz), 7.19-7.40(m, 4H), 7.77(s, 1H), 8.49(d, 1H, J=1.8
# Hz), 8.70(s, 1H).
164
Figure US06867221-20050315-C00366
 		74% 1.70-1.90(m, 4H), 2.08-2.18(m, 2H), 2.95-3.05(m, 2H), 3.58(s, 2H), 3.63-3.73(m, 1H), 3.87(s, 3H), 3.88(s, 6H), 3.89(s, 3H), 3.92(s, 6H), 4.50(s, 2H), 6.65- 6.72(m, 2H), 6.69(s, 2H), 6.76(s, 2H), 6.87(dd, 2H, J=9.0Hz, 9.0 Hz), 7.22(d, 1H, J=7.6Hz), 7.25-
# 7.48(m, 9H).
PREPARATION EXAMPLE 186 Synthesis of 1-(tert-butoxycarbonyl)-4-phenylaminopiperidine
Figure US06867221-20050315-C00367
1-(tert-Butoxycarbonyl)-4-piperidone (5.00 g) and aniline (2.23 g) was treated in the same manner as described in Preparation Example 37 to give white needles of the title compound.
Yield: 3.77 g (57%). 1H-NMR (400 MHz, CDCl3) δ: 1.25-1.38 (m, 2H), 1.47 (s, 9H), 2.00-2.07 (m, 2H), 2.87-2.97 (m, 2H), 3.38-3.53 (m, 2H), 3.96-4.14 (m, 2H), 6.57-6.52 (m, 2H), 6.70 (tt, 1H, J=6.2 Hz, 1.0 Hz), 7.17 (dd, 2H, J=8.6 Hz, 7.2 Hz).
PREPARATION EXAMPLE 187 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-phenyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00368
1-(tert-Butoxycarbonyl)-4-phenylaminopiperidine (553 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 760 mg (71%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.53-1.63 (m, 2H), 1.83-1.91 (m, 2H), 2.76-2.90 (m, 2H), 3.86-3.97 (m, 1H), 3.89 (s, 3H), 3.93 (s, 6H), 4.14-4.32 (m, 2H), 4.49 (s, 2H), 6.71-6.78 (m, 3H), 7.14 (s, 1H), 7.15 (s, 2H), 7.21 (dd, 2H, J=8.8 Hz, 7.4 Hz), 7.55 (s, 1H), 8.56 (d, 1H, J=5.1 Hz).
PREPARATION EXAMPLE 188 Synthesis of 4-[N-phenyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00369
1-(tert-Butoxycarbonyl)-4-[N-phenyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine (760 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 652 mg (90%).
PREPARATION EXAMPLE 189 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-phenyl-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00370
1-(tert-Butoxycarbonyl)-4-phenylaminopiperidine (553 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 222 mg (21%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.52-1.67 (m, 2H), 1.82-1.91 (m, 2H), 2.74-2.87 (m, 2H), 3.88-3.90 (m, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 4.14-4.31 (m, 2H), 4.53 (s, 2H), 6.67 (s, 2H), 6.74-6.80 (m, 3H), 7.21 (dd, 2H, J=8.8 Hz, 7.2 Hz), 7.67 (s, 1H), 8.50 (d, 1H, J=5.3 Hz, 2.2 Hz), 8.66 (d, 1H, J=2.1 Hz).
PREPARATION EXAMPLE 190 Synthesis of 4-[N-phenyl-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00371
1-(tert-Butoxycarbonyl)-4-[N-phenyl-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine (222 mg) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 197 mg (94%).
PREPARATION EXAMPLE 191 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-phenyl-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine
Figure US06867221-20050315-C00372
1-(tert-Butoxycarbonyl)-4-phenylaminopiperidine (553 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Yield: 1.06 g (100%). 1H-NMR (400 MHz, CDCl3) δ: 1.45 (s, 9H), 1.52-1.68 (m, 2H), 1.83-1.92 (m, 2H), 2.73-2.86 (m, 2H), 3.88 (s, 3H), 3.89 (s, 6H), 3.94 (tt, 1H, J=11.7 Hz, 3.3 Hz), 4.14-4.30 (m, 2H), 4.52 (s, 2H), 6.69-6.78 (m, 6H), 7.17-7.27 (m, 2H), 7.32-7.42 (m, 3H).
PREPARATION EXAMPLE 192 Synthesis of 4-[N-phenyl-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine hydrochloride
Figure US06867221-20050315-C00373
1-(tert-Butoxycarbonyl)-4-[N-phenyl-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]piperidine (1.06 g) was treated in the same manner as described in Preparation Example 94 to give light yellow powder of the title compound.
Yield: 909 mg (97%).
EXAMPLES 165 TO 169
These compounds were obtained by the condensation of amines obtained in Preparation Examples 188, 190 and 192 with chloride derivatives obtained in Preparation Examples 3 and 48. Free bases obtained were then converted to the corresponding hydrochlorides. Yields and NMR data of their free bases are listed below.
Ex-
am- NMR data (400 MHz, measured as
ple Structure Yield free bases, CDCl3) δ
165
Figure US06867221-20050315-C00374
 		53% 1.63-1.81(m, 4H), 1.82-1.92(m, 2H), 2.14-2.24(m, 2H), 2.95-3.05 (m, 2H), 3.59(s, 2H), 3.80-4.02 (m, 1H), 3.89(s, 3H), 3.90(s, 3H), 3.92(s, 6H), 3.93(s, 6H), 4.53(s, 2H), 6.69-6.77(m, 5H), 7.13-7.17 (m, 3H), 7.20(dd, 2H, J=7.6Hz, 7.6Hz), 7.55(s, 1H), 7.76(s, 1H),
# 8.51(d, 1H, J=1.8Hz), 8.55(d, 1H, J=5.1Hz), 8.70(s, 1H).
166
Figure US06867221-20050315-C00375
 		50% 1.85-2.04(m, 4H), 2.20-2.40(m, 2H), 2.92-3.25(m, 2H), 3.60-3.77 (m, 3H), 3.88(s, 3H), 3.89(s, 6H), 3.90(s, 3H), 3.97(s, 6H), 4.59(s, 2H), 6.67(s, 2H), 6.72-6.81(m, 4H), 7.17-7.30(m, 4H), 7.68(s, 1H), 8.50(s, 1H), 8.62(d, 1H, J=4.9Hz , 8.65(d, 1H, J=2.0Hz).
167
Figure US06867221-20050315-C00376
 		43% 1.72-1.92(m, 4H), 2.13-2.26(m, 2H), 2.95-3.04(m, 2H), 3.59(s, 2H), 3.78-4.01(m, 1H), 3.88(s, 9H), 3.90(s, 3H), 3.93(s, 6H), 4.56(s, 2H), 6.66(s, 2H), 6.70- 6.78(m, 5H), 7.19(dd, 2H, J=8.2 Hz, 8.2Hz), 7.66(s, 1H), 7.77(s, 1H), 8.50(d, 1H, J=2.3Hz), 8.51
# (d, 1H, J=2.2Hz), 8.65(d, 1H, J=1.9Hz), 8.70(d, 1H, J=2.2Hz).
168
Figure US06867221-20050315-C00377
 		82% 1.75-1.92(m, 4H), 2.14-2.23(m, 2H), 2.94-3.01(m, 2H), 3.57(s, 2H), 3.80-3.94(m, 1H), 3.87(s, 3H), 3.88(s, 6H), 3.90(s, 3H), 3.96(s, 6H), 4.57(s, 2H), 6.67- 6.77(m, 5H), 7.15-7.27(m, 5H), 7.34(dd, 1H, J=7.4Hz, 7.4Hz), 7.39(d, 1H, 7.6Hz), 7.42(s, 1H),
# 7.59(s, 1H), 8.59(d, 1H, J=5.1 Hz).
169
Figure US06867221-20050315-C00378
 		65% 1.72-1.91(m, 4H), 2.13-2.22(m, 2H), 2.95-3.03(m, 2H), 3.59(s, 2H), 3.79-4.00(m, 1H), 3.87(s, 3H), 3.87(s, 6H), 3.90(s, 3H), 3.93(s, 6H), 4.56(s, 2H), 6.66- 6.77(m, 7H), 7.18(dd, 2H, J=7.4 Hz, 7.4Hz), 7.24(d, 1H, J=7.4 Hz), 7.33(dd, 1H, J=7.4Hz, 7.4
# Hz), 7.38(d, 1H, J=7.6Hz), 7.41 (s, 1H), 7.76(s, 1H), 8.50(d, 1H, J=1.6Hz), 8.69(d, 1H, J=2.2Hz).
PREPARATION EXAMPLES 193 TO 203
These compounds were prepared by the same procedure as described in Preparation Example from 1 to 3. Structures and NMR data are listed below.
Preparation
Example Structure NMR data (400 MHz, CDCl3) δ
193
Figure US06867221-20050315-C00379
 		4.61(s, 2H), 7.25(d, 1H, J=1.2Hz), 7.41-7.52 (m, 3H), 7.75(d, 1H, J=0.8Hz), 7.98-8.02(m, 2H), 8.69(d, 1H, J=4.9Hz).
194
Figure US06867221-20050315-C00380
 		3.87(s, 3H), 4.60(s, 2H), 7.01(d, 1H, J=8.4Hz), 7.08(t, 1H, J=7.4Hz), 7.24(dd, 1H, J=5.1Hz, 1.4Hz), 7.38(dt, 1H, J=7.4Hz, 1.8Hz), 7.77 (dd, 1H, J=7.6Hz, 1.8Hz), 7.84(s, 1H), 8.69(d, 1H, J=5.1Hz)
195
Figure US06867221-20050315-C00381
 		3.90(s, 3H), 4.60(s, 2H), 6.87-7.03(1H, m), 7.39(t, 1H, 7.8Hz), 7.50-7.66(m, 2H), 7.73(s, 1H), 8.68(d, 1H, J=5.1Hz)
196
Figure US06867221-20050315-C00382
 		1.45(t, 3H, J=7.0Hz), 4.12(q, 2H, J=7.0Hz), 4.59(s, 2H), 6.99(d, 2H, J=8.8Hz), 7.18(d, 1H, J=5.1Hz), 7.20-7.29(m, 1H), 7.68(s, 1H), 7.95 (d, 2H, J=8.8Hz), 8.63(d, 1H, J=5.1Hz)
197
Figure US06867221-20050315-C00383
 		3.95(s, 3H), 4.00(s, 3H), 4.60(s, 2H), 6.96(d, 1H, J=8.4Hz), 7.21(d, 1H, J=4.1Hz), 7.53(dd, 1H, J=8.4Hz, 2.0Hz), 7.67(d, 1H, J=2.0Hz), 7.70(s, 1H), 8.65(d, 1H, J=5.1Hz)
198
Figure US06867221-20050315-C00384
 		4.61(s, 2H), 7.14-7.21(m, 1H), 7.21-7.23(m, 2H), 7.35-7.42(m, 1H), 7.80(s, 1H), 7.98(1H, dt, J=8.0Hz, 2.0Hz), 8.73(d, 1H, J=5.1Hz)
199
Figure US06867221-20050315-C00385
 		4.61(s, 2H), 7.13(1H, dt, J=8.4Hz, 2.8Hz), 7.28 (1H, d, J=5.0Hz), 7.40-7.79(m, 1H), 7.70-7.79 (m, 3H), 8.69(d, 1H, J=5.0Hz)
200
Figure US06867221-20050315-C00386
 		4.60(s, 2H), 7.13-7.20(m, 2H), 7.25(1H, d, J=5.1Hz), 7.70(s, 1H), 7.95-8.03(m, 2H), 8.66 (d, 1H, J=5.1Hz)
201
Figure US06867221-20050315-C00387
 		4.61(s, 2H), 7.21-7.30(m, 2H), 7.69(s, 1H), 7.73-7.76(m, 1H), 7.85-7.92(m, 1H), 8.76(d, 1H, J=4.9Hz)
202
Figure US06867221-20050315-C00388
 		4.61(s, 2H), 6.86-6.91(m, 1H), 7.31(1H, d, J=5.1Hz), 7.51-7.59(m, 2H), 7.71(s, 1H), 8.69 (d, 1H, J=5.1Hz)
203
Figure US06867221-20050315-C00389
 		4.61(s, 2H), 7.26(d, 1H, J=4.9Hz), 7.45(d, 2H, J=8.4Hz), 7.72(s, 1H), 7.95(d, 2H, J=8.4Hz), 8.68(s, 1H, J=4.9Hz)
PREPARATION EXAMPLE 204 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[(2-phenylpyridin-4-yl)methyl]amino]piperidine
Figure US06867221-20050315-C00390
4-p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (612 mg) and 4-chloromethyl -2-phenylpyridine (204 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Yield: 407 mg (43%).
PREPARATION EXAMPLE 205 Synthesis of 4-[N-(4-methoxyphenyl)-N-[(2-phenylpyridin-4-yl)methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00391
1-(tert-Butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[(2-phenylpyridin-4-yl)methyl]amino]piperidine (407 mg) was treated in the same manner as described in Preparation Example 94 to give the title compound.
Yield: 365 mg (95%).
PREPARATION EXAMPLE 206 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[[2-(2-methoxyphenyl)pyridin-4-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00392
4-p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl -2-(2-methoxyphenyl)pyridine (234 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Yield: 237 mg (72%).
PREPARATION EXAMPLE 207 Synthesis of 4-[N-(4-methoxyphenyl)-N-[[2-(2-methoxyphenyl)pyridin-4-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00393
1-(tert-Butoxycarbonyt)-4-[N-(4-methoxyphenyl)-N-[[2-(2-methoxyphenyl)pyridin-4-yl]methyl]amino]piperidine (360 mg) was treated in the same manner as described in Preparation Example 94 to give the title compound.
Yield: 365 mg (65%).
PREPARATION EXAMPLE 208 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[[2-(3-methoxyphenyl)pyridin-4-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00394
4-p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(3-methoxyphenyl)pyridine (234 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Yield: 550 mg (theoretical yield).
PREPARATION EXAMPLE 209 Synthesis of 4-[N-(4-methoxyphenyl)-N-[[2-(3-methoxyphenyl)pyridin-4-yl]methyl]amino]piperidine dihydrochloride
Figure US06867221-20050315-C00395
1-(tert-Butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[[2-(3-methoxyphenyl)pyridin-4-yl]methyl]amino]piperidine (550 mg) was treated in the same manner as described in Preparation Example 94 to give the title compound.
Yield: 436 g (85%).
PREPARATION EXAMPLE 210 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[2-(4-ethoxyphenyl)pyridin-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine
Figure US06867221-20050315-C00396
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(4-ethoxyphenyl)pyridine (248 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Yield: 515 mg (99%).
PREPARATION EXAMPLE 211 Synthesis of 4-[N-[2-(4-ethoxyphenyl)pyridin-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine dihydrochloride
Figure US06867221-20050315-C00397
1-(tert-Butoxycarbonyl)-4-[N-[2-(4-ethoxyphenyl)pyridin-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine (515 mg) was treated in the same manner as described in Preparation Example 94 to give the title compound.
Yield: 418 mg (80%).
PREPARATION EXAMPLE 212 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-(4-methoxyphenyl)-N-[[2-(3,4-dimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine
Figure US06867221-20050315-C00398
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(3,4-dimethoxyphenyl)pyridine (264 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Yield: 600 mg (theoretical yield).
PREPARATION EXAMPLE 213 Synthesis of 4-[N-[2-(3,4-dimethoxyphenyl)pyridin-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine dihydrochloride
Figure US06867221-20050315-C00399
1-(tert-Butoxycarbonyl)-4-[N-[2-(3,4-dimethoxyphenyl)pyridin-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine (600 mg) was treated in the same manner as described in Preparation Example 94 to give the title compound.
Yield: 416 mg (77%).
PREPARATION EXAMPLE 214 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[2-(2-fluorophenyl)pyridin-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine
Figure US06867221-20050315-C00400
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(2-fluorophenyl)pyridine (222 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Yield: 530 mg (theoretical yield).
PREPARATION EXAMPLE 215 Synthesis of 4-[N-[2-(2-fluorophenyl)pyridin-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine dihydrochloride
Figure US06867221-20050315-C00401
1-(tert-Butoxycarbonyl)-4-[N-[2-(2-fluorophenyl)pyridin-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine (530 mg) was treated in the same manner as described in Preparation Example 94 to give the title compound.
Yield: 423 mg (85%).
PREPARATION EXAMPLE 216 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[2-(3-fluorophenyl)pyridin-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine
Figure US06867221-20050315-C00402
4-p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (153 mg) and 4-chloromethyl-2-(3-fluorophenyl)pyridine (111 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Yield: 270 mg (theoretical yield).
PREPARATION EXAMPLE 217 Synthesis of 4-[N-[2-(3-fluorophenyl)pyridin-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine dihydrochloride
Figure US06867221-20050315-C00403
1-(tert-Butoxycarbonyl)-4-[N-[2-(3-fluorophenyl)pyridin-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine (270 mg) was treated in the same manner as described in Preparation Example 94 to give the title compound.
Yield: 193 mg (70%).
PREPARATION EXAMPLE 218 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[2-(4-fluorophenyl)pyridin-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine
Figure US06867221-20050315-C00404
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(4-fluorophenyl)pyridine (222 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Yield: 550 mg (theoretical yield).
PREPARATION EXAMPLE 219 Synthesis of 4-[N-[2-(4-fluorophenyl)pyridin-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine dihydrochloride
Figure US06867221-20050315-C00405
1-(tert-Butoxycarbonyl)-4-[N-[2-(4-fluorophenyl)pyridin-4-yl]methyl-N-(4-m ethoxyphenyl)amino]piperidine (550 mg) was treated in the same manner as described in Preparation Example 94 to give the title compound.
Yield: 439 mg (88%).
PREPARATION EXAMPLE 220 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[2-(3,4-difluorophenyl)pyridin-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine
Figure US06867221-20050315-C00406
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(3,4-difluorophenyl)pyridine (240 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Yield: 590 mg (theoretical yield).
PREPARATION EXAMPLE 221 Synthesis of 4-[N-[2-(3,4-difluorophenyl)pyridin-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine dihydrochloride
Figure US06867221-20050315-C00407
1-(tert-Butoxycarbonyl)-4-[-N-[2-(3,4-difluorophenyl)pyridin-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine (590 mg) was treated in the same manner as described in Preparation Example 94 to give the title compound.
Yield: 483 mg (93%).
PREPARATION EXAMPLE 222 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[2-(3,5-difluorophenyl)pyridin-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine
Figure US06867221-20050315-C00408
4-p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(3,5-difluorophenyl)pyridine (240 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Yield: 530 mg (theoretical yield).
PREPARATION EXAMPLE 223 Synthesis of 4-[N-[2-(3,5-difluorophenyl)pyridin-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine dihydrochloride
Figure US06867221-20050315-C00409
1-(tert-Butoxycarbonyl)-4-[N-[2-(3,5-difluorophenyl)pyridin-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine: (530 mg) was treated in the same manner as described in Preparation Example 94 to give the title compound.
Yield: 418 mg (81%).
PREPARATION EXAMPLE 224 Synthesis of 1-(tert-butoxycarbonyl)-4-[N-[2-(4-chlorophenyl)pyridin-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine
Figure US06867221-20050315-C00410
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(4-chlorophenyl)pyridine (238 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Yield: 600 mg (theoretical yield).
PREPARATION EXAMPLE 225 Synthesis of 4-[N-[2-(4-chlorophenyl)pyridin-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine dihydrochloride
Figure US06867221-20050315-C00411
1-(tert-Butoxycarbonyl)-4-[N-[2-(4-chlorophenyl)pyridin-4-yl]methyl-N-(4-methoxyphenyl)amino]piperidine: (600 mg) was treated in the same manner as described in Preparation Example 94 to give the title compound.
Yield: 447 mg (86%).
EXAMPLES 170 TO 202
These compounds were obtained by the condensation of amines obtained in Preparation Examples 96, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223 and 225 with chloride derivatives obtained in Preparation Examples 3, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102 and 103. Free bases obtained were then converted to the corresponding hydrochlorides. Yields and NMR data of their free bases are listed below.
Ex-
am- NMR data (400 MHz, measured as
ple Structure Yield free bases, CDCl3) δ
170
Figure US06867221-20050315-C00412
 		 47% 1.67-1.80(m, 2H), 1.83-1.91(m, 2H), 2.10-2.19(m, 2H), 2.93-3.00 (m, 2H), 3.54-3.65(m, 1H), 3.56 (s, 2H), 3.73(s, 3H), 3.89(s, 3H), 3.93(s, 6H), 4.45(s, 3H), 6.73(d, 2H, J=9.4Hz), 6.78(d, 2H, J=9.4 Hz), 7.14-7.21(m, 2H), 7.15(s, 2H), 7.38-7.49(m, 3H), 7.57(s, 1H), 7.68(s, 1H), 7.97(d, 1H,
# J=1.0Hz), 7.99(d, 1H, J=1.6Hz), 8.54(d, 1H, J=5.1Hz), 8.61(d, 1H, J=5.1Hz).
171
Figure US06867221-20050315-C00413
 		 55% 1.62-1.80(m, 2H), 1.84-1.93(m, 2H), 2.10-2.20(m, 2H), 2.93-3.02 (m, 2H), 3.53-3.66(m, 1H), 3.56 (s, 2H), 3.73(s, 3H), 3.90(s, 3H), 3.96(s, 6H), 4.44(s, 2H), 6.65- 6.83(m, 4H), 7.14-7.30(m, 4H), 7.36-7.50(m, 3H), 7.59(s, 1H), 7.67(s, 1H), 7.93(d, 2H, J=7.0 Hz), 8.54-8.61(m, 2H).
172
Figure US06867221-20050315-C00414
 		 54% 1.67-1.92(m, 4H), 2.08-2.20(m, 2H), 2.92-3.01(m, 2H), 3.52-3.65 (m, 1H), 3.55(s, 2H), 3.72(s, 3H), 4.38(s, 2H), 6.72(d, 2H, J=9.2 Hz), 6.78(d, 2H, J=9.0Hz), 7.18 (dd, 2H, J=4.9Hz, 4.9Hz), 7.36- 7.50(m, 6H), 7.67(s, 1H), 7.68(s, 1H), 7.93(dd, 2H, J=8.4Hz, 1.2 Hz), 7.98(dd, 2H, J=8.6Hz, 1.4
# Hz), 8.57(d, 1H, J=5.1Hz), 8.60 (d, 1H, J=s,1Hz).
173
Figure US06867221-20050315-C00415
 		100% 1.66-1.79(m, 2H), 1.82-1.91(m, 2H), 2.09-2.20(m, 2H), 2.93-3.03 (m, 2H), 3.56(s, 2H), 3.56-3.59 (m, 1H), 3.73(s, 3H), 3.80(s, 3H), 3.89(s, 3H), 3.93(s, 6H), 4.45(s, 2H), 6.73(d, 2H, J=9.3Hz), 6.78 (d, 2H, J=9.3Hz), 6.98(d, 1H, J=8.5Hz), 7.07(t, 1H, J=7.6Hz), 7.15(s, 2H), 7.15-7.19(m, 2H),
# 7.33-7.38(m, 1H), 7.57(s, 1H), 7.66-7.74(m, 2H), 8.53(d, 1H, J=5.1Hz), 8.61(d, 1H, J=4.9Hz).
174
Figure US06867221-20050315-C00416
 		 94% 1.70-1.80(m, 2H), 1.83-1.91(m, 2H), 2.11-2.18(m, 2H), 2.92-3.01 (m, 2H), 3.56(s, 2H), 3.57-3.65 (m, 1H), 3.73(s, 3H), 3.74(s, 3H), 3.90(s, 3H), 3.96(s, 6H), 4.44(s, 2H), 6.71(d, 2H, J=9.0Hz), 6.78 (d, 2H, J=9.0Hz), 6.96(d, 1H, J=8.3Hz), 7.05(dt, 1H, J=7.3Hz, 1.0Hz), 7.14(d, 1H, J=5.2Hz),
# 7.20(d, 1H, J=5.2Hz), 7.22(2H, s), 7.32-7.37(m, 1H), 7.59(s, 1H), 7.71-7.75(m, 2H), 8.56-8.60(m, 2H).
175
Figure US06867221-20050315-C00417
 		 98% 1.67-1.80(m, 2H), 1.83-1.90(m, 2H), 2.10-2.19(m, 2H), 2.94-3.03 (m, 2H), 3.50-3.67(m, 1H), 3.56 (s, 2H), 3.73(s, 3H), 3.74(s, 3H), 3.79(s, 3H), 4.44(s, 2H), 6.70(d, 2H, J=9.3Hz), 6.78(d, 2H, J=9.3 Hz), 6.96(d, 1H, J=8.3Hz), 6.98 (d, 1H, J=8.8Hz), 7.04(dd, 1H), J=7.6Hz, 1.0Hz), 7.07 (dd, 1H, 7.6, J=1.0Hz), 7.12-7.19
# (m, 2H), 7.32-7.39(m, 2H), 7.70- 7.75(m, 4H), 8.58(d, 1H, J= 5.1Hz), 8.61 (d, 1H, J=4.9Hz).
176
Figure US06867221-20050315-C00418
 		100% 1.68-1.79(m, 2H), 1.82-1.90(m, 2H), 2.10-2.19(m, 2H), 2.90-3.01 (m, 2H), 3.56(s, 2H), 3.56-3.58 (m, 1H), 3.73(s, 3H), 3.89(s, 3H), 3.91(s, 3H), 3.93(s, 6H), 4.45(s, 2H), 6.73(d, 2H, J=9.3Hz), 6.78 (d, 2H, J=9.3Hz), 6.93-6.99(m, 1H), 7.15(s, 2H), 7.16-7.20(m, 2H), 7.37(t, 1H, J=7.8Hz), 7.52-
# 7.59(m, 3H), 7.67(s, 1H), 8.54 (d, 1H, J=5.1Hz), 8.60(d, 1H, J=5.1Hz).
177
Figure US06867221-20050315-C00419
 		100% 1.68-1.79(m, 2H), 1.83-1.92(m, 2H), 2.11-2.16(m, 2H), 2.91-3.02 (m, 2H), 3.56(s, 2H), 3.55-3.65 (m, 1H), 3.73(s, 3H), 3.88(s, 3H), 3.90(s, 3H), 3.96(s, 6H), 4.43(s, 2H), 6.72(d, 2H, J=9.3Hz), 6.78 (d, 2H, J=9.3Hz), 6.95(dd, 1H. J=8.3Hz, 2.7Hz), 7.16-7.21(m, 2H), 7.22(s, 2H), 7.35(t, 1H,
# J=7.8Hz), 7.48(d, 1H, J=7.8Hz), 7.53(t, 1H, J=2.7Hz), 7.59(s, 1H), 7.65(s, 1H), 8.55-8.60(m, 2H).
178
Figure US06867221-20050315-C00420
 		100% 1.65-1.79(m, 2H), 1.82-1.90(m, 2H), 2.09-2.19(m, 2H), 2.92-3.00 (m, 2H), 3.50-3.66(m, 1H), 3.56 (s, 2H), 3.73(s, 3H), 3.73(s, 3H), 3.88(s, 3H), 3.89(s, 3H), 4.44(s, 2H), 6.72(d, 2H, J=9.3Hz), 6.78 (d, 2H, J=9.3Hz), 6.92-6.98(m, 2H), 7.16-7.21(m, 2H), 7.34(d, 1H, J=7.8Hz), 7.38(d, 1H, J=8.5
# Hz), 7.46-7.59(m, 4H), 7.65(s, 1H), 7.67(s, 1H), 8.57(dd, 1H, J=5.1Hz, 0.7Hz), 8.60(d, 1H, J=5.1Hz).
179
Figure US06867221-20050315-C00421
 		 76% 1.44(t, 3H, J=7.1Hz), 1.70-1.80 (m, 2H), 1.82-1.91(m, 2H), 2.10- 2.19(m, 2H), 2.90-3.02(m, 2H), 3.54(s, 2H), 3.73-3.78(m, 1H), 3.73(s, 3H), 3.88(s, 3H), 3.93(s, 6H), 4.09(q, 2H, J=7.1Hz), 4.45 (s, 2H), 6.73(d, 2H, J=9.2Hz), 6.78(d, 2H, J=9.2Hz), 6.97(d, 2H, J=8.8Hz), 7. 10-7.18(m, 2H),
# 7.15(s, 2H), 7.57(s, 1H), 7.61(s, 1H), 7.92(d, 2H, J=8.8Hz), 8.52- 8.58(m, 2H).
180
Figure US06867221-20050315-C00422
 		 93% 1.43(t, 3H, J=6.8Hz), 1.68-1.80 (m, 2H), 1.82-1.92(m, 2H), 2.10- 2.19(m, 2H), 2.90-3.01(m, 2H), 3.56(s, 2H), 3.57-3.64(m, 1H), 3.73(s, 3H), 3.90(s, 3H), 3.96(s, 6H), 4.08(q, 2H, J=6.8Hz), 4.42 (s, 2H), 6.72(d, 2H, J=9.0Hz), 6.78(d, 2H, J=9.3Hz), 6.95(d, 2H, J=8.8Hz), 7.11(d, 1H, J=5.1
# Hz), 7.20(d, 1H, J=5.1Hz), 7.22 (s, 2H), 7.58-7.62(m, 2H), 7.87 (d, 2H, J=8.8Hz), 8.52(d, 1H, J=5.1Hz), 8.58(d, 1H, J=5.1Hz).
181
Figure US06867221-20050315-C00423
 		100% 1.43(t, 3H, J=7.1Hz), 1.44(t, 3H, J=7.1Hz), 1.67-1.78(m, 2H), 1.82-1.90(m, 2H), 2.09-2.18(m, 2H), 2.92-3.00(m, 2H), 3.54(s, 2H), 3.55-3.65(m, 1H), 3.73(s, 3H), 4.08(q, 2H, J=7.1Hz), 4.09 (q, 2H, J=6.8Hz), 4.42(s, 2H), 6.71(d, 2H, J=9.0Hz), 6.78(d, 2H, J=9.0Hz), 6.93-7.00(m, 4H),
# 7.10-7.14(m, 2H), 7.60(s, 2H), 7.88(s, 2H), 7.88(d, 2H, J=8.8 Hz), 7.93(d, 2H, J=8.8Hz), 8.52 (d, 1H, J=5.1Hz), 8.56(d, 1H, J=4.9Hz).
182
Figure US06867221-20050315-C00424
 		100% 1.68-1.79(m, 2H), 1.82-1.90(m, 2H), 2.10-2.19(m, 2H), 2.90-3.01 (m, 2H), 3.55(s, 2H), 3.56-3.59 (m, 1H), 3.73(s, 3H), 3.89(s, 3H), 3.93(s, 6H), 3.94(s, 3H), 3.99(s, 3H), 4.45(s, 2H), 6.76(d, 2H, J=9.5Hz), 6.78(d, 2H, J=9.5Hz), 6.94(d, 1H, J=8.3Hz), 7.15(s, 2H), 7.16-7.19(m, 2H), 7.49-7.66
# (m, 4H), 8.54(d, 1H, J=4.9Hz), 8.57(d, 1H, J=5.1Hz).
183
Figure US06867221-20050315-C00425
 		100% 1.68-1.78(m, 2H), 1.82-1.91(m, 2H), 2.10-2.18(m, 2H), 2.93-3.00 (m, 2H), 3.56(s, 2H), 3.56-3.62 (m, 1H), 3.73(s, 3H), 3.90(s, 3H), 3.93(s, 3H), 3.96(s, 6H), 3.97(S, 3H), 4.43(s, 2H), 6.72(d, 2H, J=9.3Hz), 6.78(d, 2H, J=9.3Hz), 6.92(d, 1H, J=8.3Hz), 7.12(d, 1H, J=5.1Hz), 7.20(d, 1H, J=5.1
# Hz), 7.22(s, 2H), 7.42(d, 1H, J=8.5Hz, 2.2Hz), 7.58-7.63(m, 3H), 8.53(d, 1H, J=4.9Hz), 8.58 (d, 1H, J=5.1Hz).
184
Figure US06867221-20050315-C00426
 		 89% 1.67-1.79(m, 2H), 1.84-1.90(m, 2H), 2.10-2.19(m, 2H), 2.93-3.01 (m, 2H), 3.50-3.65(m, 1H), 3.55 (s, 2H), 3.73(s, 3H), 3.94(s, 3H), 3.97(s, 3H), 3.99(s, 3H), 4.43(s, 2H), 6.72(d, 2H, J=9.3Hz), 6.78 (d, 2H, J=9.3Hz), 6.92(d, 1H, J=8.6Hz), 6.94(d, 1H, J=8.3Hz), 7.14(d, 1H, J=5.6Hz), 7.15(d,
# 1H, J=6.4Hz), 7.43(dd, 1H, J=8.6 Hz, 2.0Hz), 7.50(dd, 1H, J=8.3 Hz, 1.9Hz), 7.60-7.63(m, 3H), 7.66(d, 1H, J=2.2Hz), 8.53(d, 1H, J=5.1Hz), 8.57(d, 1H, J=4.9 Hz).
185
Figure US06867221-20050315-C00427
 		100% 1.68-1.79(m, 2H), 1.82-1.90(m, 2H), 2.10-2.20(m, 2H), 2.93-3.01 (m, 2H), 3.57(s, 2H), 3.57-3.65 (m, 1H), 3.73(s, 3H), 3.89(s, 3H), 3.93(s, 6H), 4.46(s, 2H), 6.73(d, 2H, J=7.3Hz), 6.78(d, 2H, J=7.3 Hz), 7.11-7.19(m, 2H), 7.15(s, 2H), 7.22-7.29(m, 2H), 7.34-7.40 (m, 1H), 7.58(s, 1H), 7.73(s, 1H),
# 7.94(t, 1H, J=8.3Hz), 8.54(d, 1H, J=5.1Hz), 8.64(d, 1H, J=4.9 Hz).
186
Figure US06867221-20050315-C00428
 		 88% 1.68-1.79(m, 2H), 1.83-1.92(m, 2H), 2.09-2.16(m, 2H), 2.93-3.01 (m, 2H), 3.56(s, 2H), 3.56-3.62 (m, 1H), 3.73(s, 3H), 3.90(s, 3H), 3.96(s, 6H), 4.44(s, 2H), 6.71(d, 2H, J=9.3Hz), 6.77(d, 2H, J=9.3 Hz), 7.10-7.16(m, 1H), 7.17-7.26 (m, 3H), 7.22(s, 2H), 7.32-7.38 (m, 1H), 7.59(s, 1H), 7.73(s,
# 1H), 7.92(dt, 1H, J=8.0Hz, 2.0 Hz), 8.57-8.61(m, 2H).
187
Figure US06867221-20050315-C00429
 		100% 1.66-1.80(m, 2H), 1.83-1.93(m, 2H), 2.10-2.20(m, 2H), 2.92-3.02 (m, 2H), 3.53-3.65(m, 1H), 3.57 (s, 2H), 3.73(s, 3H), 4.44(s, 2H), 6.71(d, 2H, J=9.0Hz), 6.78(d, 2H, J=9.3Hz), 7.10-7.18(m, 2H), 7.19-7.29(m, 4H), 7.32-7.40(m, 2H), 7.73(s, 2H), 7.91(dd, 1H, J=8.1Hz, 1.4Hz), 7.95(dd, 1H,
# J=7.6Hz, 1.5Hz), 8.60(d, 1H, J=4.9Hz), 8.64(d, 1H, J=5.1Hz).
188
Figure US06867221-20050315-C00430
 		 96% 1.67-1.80(m, 2H), 1.82-1.92(m, 2H), 2.10-2.20(m, 2H), 2.91-3.01 (m, 2H), 3.56(s, 2H), 3.56- 3.61(m, 1H), 3.73(s, 3H), 3.89(s, 3H), 3.93(s, 6H), 4.46(s, 2H), 6.73(d, 2H, J=9.3Hz), 6.78(d, 2H, J=9.3Hz), 7.06-7.19(m, 2H), 7.15(s, 2H), 7.20-7.26(m, 1H), 7.38-7.45(m, 1H), 7.56(s, 1H),
# 7.66-7.78(m, 3H), 8.54(d, 1H, J=5.1Hz), 8.61(d, 1H, J=4.9Hz).
189
Figure US06867221-20050315-C00431
 		 92% 1.65-1.78(m, 2H), 1.79-1.92(m, 2H), 2.21-2.26(m, 2H), 2.90-3.01 (m, 2H), 3.56(s, 2H), 3.56-3.63 (m, 1H), 3.73(s, 3H), 3.90(s, 3H), 3.96(s, 6H), 4.44(s, 2H), 6.72(d, 2H, J=9.3Hz), 6.78(d, 2H, J=9.3 Hz), 7.08(dt, 1H, J=8.3Hz, 1.7 Hz), 7.18-7.40(m, 2H), 7.22(s, 2H), 7.37-7.43(m, 1H), 7.56-7.72
# (m, 4H), 8.55-8.60(m, 2H).
190
Figure US06867221-20050315-C00432
 		 55% 1.66-1.79(m, 2H), 1.80-1.91(m, 2H), 2.10-2.20(m, 2H), 2.88-3.01 (m, 2H), 3.50-3.66(m, 1H), 3.56 (s, 2H), 3.73(s, 3H), 4.45(s, 2H), 6.72(d, 2H, J=8.5Hz), 6.79(d, 2H, J=9.0Hz), 7.04-7.13(m, 2H), 7.19-7.25(m, 2H), 7.35-7.46(m, 2H), 7.62-7.79(m, 6H), 8.57(d, 1H, J=5.1Hz), 8.61(d, 1H, J=4.9
# Hz).
191
Figure US06867221-20050315-C00433
 		100% 1.68-1.79(m, 2H), 1.82-1.91(m, 2H), 2.10-2.19(m, 2H), 2.92-3.00 (m, 2H), 3.55(s, 2H), 3.56-3.63 (m, 1H), 3.73(s, 3H), 3.89(s, 3H), 3.93(s, 6H), 4.45(s, 2H), 6.73(d, 2H, J=9.3Hz), 6.78(d, 2H, J=9.3 Hz), 7.11-7.19(m, 4H), 7.15(s, 2H), 7.57(s, 1H), 7.63(s, 1H), 7.92-8.01(m, 2H), 8.54(d, 1H,
# J=5.1Hz), 8.58(d, 1H, J=5.1Hz).
192
Figure US06867221-20050315-C00434
 		100% 1.68-1.79(m, 2H), 1.83-1.92(m, 2H), 2.11-2.19(m, 2H), 2.93-3.01 (m, 2H), 3.56(s, 2H), 3.57-3.62 (m, 1H), 3.73(s, 3H), 3.90(s, 3H), 3.96(s, 6H), 4.43(s, 2H), 6.72(d, 2H, J=9.3Hz), 6.78(d, 2H, J=9.3 Hz), 7.10-7.22(m, 4H), 7.22(s, 2H), 7.54-7.66(m, 2H), 7.88-7.94 (m, 2H), 8.55(d, 1H, J=4.9Hz),
# 8.58(d, 1H, J=4.9Hz).
193
Figure US06867221-20050315-C00435
 		 90% 1.66-1.80(m, 2H), 1.83-1.91(m, 2H), 2.10-2.19(m, 2H), 2.92-3.00 (m, 2H), 3.50-3.66(m, 1H), 3.55 (s, 2H), 3.73(s, 3H), 4.44(s, 2H), 6.72(d, 2H, J=9.3Hz), 7.78(d, 2H, J=9.3Hz), 7.09-7.20(m, 6H), 7.62(s, 1H), 7.63(s, 1H), 7.89- 8.00(m, 4H), 8.55(d, 1H, J=5.1 Hz), 8.58(d, 1H, J=4.9Hz).
194
Figure US06867221-20050315-C00436
 		 36% 1.68-1.80(m, 2H), 1.82-1.90(m, 2H), 2.11-2.19(m, 2H), 2.91-2.99 (m, 2H), 3.55(s, 2H), 3.56-3.62 (m, 1H), 3.73(s, 3H), 3.89(s, 3H), 3.93(s, 6H), 4.45(s, 2H), 6.73(d, 2H, J=9.3Hz), 6.78(d, 2H, J=9.3 Hz), 7.15(s, 2H), 7.16-7.26(m, 3H), 7.57(s, 1H), 7.62(s, 1H), 7.71(br, 1H), 7.80-7.90(m, 1H),
# 8.54(d, 1H, J=5.1Hz), 8.58(d, 1H, J=4.9Hz).
195
Figure US06867221-20050315-C00437
 		100% 1.60-1.80(m, 2H), 1.82-1.91(m, 2H), 2.12-2.19(m, 2H), 2.91-3.00 (m, 2H), 3.56(s, 2H), 3.56-3.64 (m, 1H), 3.73(s, 3H), 3.90(s, 3H), 3.96(s, 6H), 4.45(s, 2H), 6.72(d, 2H, J=9.0Hz), 6.78(d, 2H, J=9.0 Hz), 7.17-7.24(m, 4H), 7.25-7.27 (m, 1H), 7.60(s, 2H), 7.65(br, 1H), 7.77-7.84(m, 1H), 8.53-8.61
# (m, 2H).
196
Figure US06867221-20050315-C00438
 		100% 1.66-1.79(m, 2H), 1.82-1.91(m, 2H), 2.09-2.20(m, 2H), 2.90-3.00 (m, 2H), 3.50-3.65(m, 1H), 3.55 (s, 2H), 3.73(s, 3H), 4.44(s, 2H), 6.72(d, 2H, J=9.3Hz), 6.79(d, 2H, J=9.3Hz), 7.18-7.28(m, 4H), 7.60(s, 1H), 7.62(s, 1H), 7.63- 7.68(m, 1H), 7.70-7.75(m, 1H), 7.77-7.89(m, 2H), 8.55(d, 1H,
# J=4.9Hz), 8.58(d, 1H, J=5.1Hz).
197
Figure US06867221-20050315-C00439
 		100% 1.68-1.80(m, 2H), 1.82-1.90(m, 2H), 2.10-2.21(m, 2H), 2.90-3.00 (m, 2H), 3.56(s, 2H), 3.56-3.63 (m, 1H), 3.73(s, 3H), 3.89(s, 3H), 3.93(s, 6H), 4.56(s, 2H), 6.73(d, 2H, J=9.3Hz), 6.78(d, 2H, J=9.3 Hz), 6.81-6.87(m, 1H), 7.15(s, 2H), 7.18(d, 1H, J=4.2Hz), 7.22- 7.26(m, 1H), 7.51-7.59(m, 3H),
# 7.65(s, 1H), 8.54(d, 1H, J=4.9 Hz), 8.59(d, 1H, J= 5.1Hz).
198
Figure US06867221-20050315-C00440
 		100% 1.65-1.79(m, 2H), 1.80-1.94(m, 2H), 2.22-2.25(m, 2H), 2.90-3.05 (m, 2H), 3.56(s, 2H), 3.56-3.65 (m, 1H), 3.73(s, 3H), 3.90(s, 3H), 3.96(s, 6H), 4.44(s, 2H), 6.72(d, 2H, J=9.2Hz), 6.78(d, 2H, J=9.2 Hz), 6.80-6.94(m, 2H), 7.22(s, 2H), 7.19-7.28(m, 1H), 7.45-7.51 (m, 2H), 7.59(s, 1H), 7.62(s, 1H),
# 8.56(d, 1H, J=4.9Hz), 8.59(d, 1H, J=5.1Hz).
199
Figure US06867221-20050315-C00441
 		100% 1.67-1.79(m, 2H), 1.82-1.92(m, 2H), 2.12-2.20(m, 2H), 2.92-2.99 (m, 2H), 3.50-3.65(m, 1H), 3.56 (s, 2H), 3.73(s, 3H), 4.45(s, 2H), 6.72(d, 2H, J=9.0Hz), 6.79(d, 2H, J=9.3Hz), 6.80-6.88(m, 2H), 7.23-7.27(m, 2H), 7.48(dd, 2H, J=8.8Hz, 2.2Hz), 7.55(dd, 2H, J=8.8Hz, 2.2Hz), 7.63(s, 1H),
# 7.65(s, 1H), 8.57(d, 1H, J=4.9 Hz), 8.60(d, 1H, J=4.9Hz).
200
Figure US06867221-20050315-C00442
 		 84% 1.68-1.80(m, 2H), 1.83-1.92(m, 2H), 2.10-2.21(m, 2H), 2.91-3.00 (m, 2H), 3.56(s, 2H), 3.57-3.62 (m, 1H), 3.73(s, 3H), 3.89(s, 3H), 3.93(s, 6H), 4.45(s, 2H), 6.73(d, 2H, J=9.3Hz), 6.78(d, 2H, J=9.3 Hz), 7.15(s, 2H), 7.17(d, 1H, J=4.9Hz), 7.20(d, 1H, J=5.1Hz), 7.43(d, 2H, J=8.3Hz), 7.57(s,
# 1H), 7.65(s, 1H), 7.93(d, 2H, J=8.3Hz), 8.54(d, 1H, J=4.9Hz), 8.59(d, 1H, J=5.1Hz).
201
Figure US06867221-20050315-C00443
 		 72% 1.65-1.78(m, 2H), 1.82-1.91(m, 2H), 2.10-2.16(m, 2H), 2.91-3.02 (m, 2H), 3.56(s, 2H), 3.56-3.64 (m, 1H), 3.73(s, 3H), 3.90(s, 3H), 3.96(s, 6H), 4.43(s, 2H), 6.72(d, 2H, J=9.3Hz), 6.78(d, 2H, J=9.3 Hz), 7.17-7.21(m, 1H), 7.22(2H, s), 7.41(d, 2H, J=8.7Hz), 7.48(d, 1H, J=7.8Hz), 7.59(s, 1H), 7.63
# (s, 1H) 7.87(d, 2H, J=8.7Hz), 8.56(d, 1H, J=4.9Hz), 8.58(d, 1H, J=5.1Hz).
202
Figure US06867221-20050315-C00444
 		 94% 1.67-1.88(m, 2H), 1.83-1.90(m, 2H), 2.10-2.17(m, 2H), 2.92-2.99 (m, 2H), 3.50-3.65(m, 1H), 3.55 (s, 2H), 3.73(s, 3H), 4.44(s, 2H), 6.72(d, 2H, J=9.OHz), 6.78(d, 2H, J=9.3Hz), 7.17-7.22(m, 2H), 7.39-7.45(m, 4H), 7.63(s, 1H), 7.65(s, 1H), 7.88(d, 2H, J=8.6 Hz), 7.93(d, 2H, J=8.5Hz), 8.56
# (d, 1H, J=4.9Hz), 8.59(d, 1H, J=4.9Hz).
PREPARATION EXAMPLE 226 Synthesis of 4-[N-[3-(3,4,5-trimethoxyphenyl)benzyl]-N-[4-(methylsulfonyl)phenyl]amino]piperidine
Figure US06867221-20050315-C00445
To a solution of 4-[N-[3-(3,4,5-trimethoxyphenyl)benzyl]-N-[4-(methylthio)phenyl]amino]piperidine hydrochloride (52 mg, obtained in the Preparation Example 145) in dichloromethane (1 mL) was added 3-chloroperbenzoic acid (69 mg) at 0° C. The mixture was stirred at room temperature for 3 hours and saturated aqueous sodium hydrogen carbonate was added. After separating the organic layer, the aqueous layer was extracted with chloroform. Organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and evaporated to give pale yellow oil of the title compound which was used for the next step without further purification.
EXAMPLE 203 Synthesis of 4-[[N-[4-(methylsulfonyl)phenyl]-N-[3-(3,4,5-trimethoxyphenyl)benzyl]amino]-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine dihydrochloride
Figure US06867221-20050315-C00446
Crude 4-[N-[3-(3,4,5-trimethoxyphenyl)benzyl]-N-[4-(methylsulfonyl)phenyl]amino]piperidine and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pylidine (29 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as pale yellow powder after converting a free base to a dihydrochloride.
Yield: 23 mg (26% in 2 steps). 1H-NMR (400 MHz, measured as a free base, CDCl3) 67 : 1.70-1.97 (m, 4H), 2.16-2.28 (m, 2H), 2.95-3.04 (m, 2H), 2.99 (s, 3H), 3.59 (s, 2H), 3.82 (s, 3H), 3.87-3.97 (m, 1H), 3.90 (s, 3H), 3.91 (s, 3H), 3.92 (s, 3H), 3.96 (s, 9H), 4.65 (s, 2H), 6.59 (s, 1H), 6.75 (d, 2H, J=9.3 Hz), 7.19-7.30 (m, 7H), 7.39 (dd, 1H, J=7.6, 7.6 Hz), 7.60 (s, 1H), 7.68 (d, 2H, J=9.0 Hz), 8.60 (d, 1H, J=4.9 Hz).
EXAMPLE 204 Synthesis of 4-[N-(4-metoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]-1-[[2-(3-methoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00447
4-[N-(4-Methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine dihydrochloride (139 mg, obtained in the Preparation Example 98) and 4-chloromethyl-2-(3-methoxyphenyl)pyridine (70 mg, obtained in the Preparation Example 195) were condensed in the same manner described in the Example 9 to give the title compound as a trihydrochloride.
Yield: 131 mg (66%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.70-1.95 (m, 4H), 2.05-2.25 (m, 2H), 2.90-3.08 (m, 2H), 3.45-3.68 (m, 3H), 3.72 (s, 3H), 3.88 (s, 3H), 3.90 (s, 9H), 4.46 (s, 2H), 6.66 (s, 2H), 6.70-6.85 (m, 4H), 6.96 (d, 1H, J=8.3 Hz), 7.21 (br, 1H), 7.38 (t, 1H, J=7.8 Hz), 7.55 (t, 1H, J=7.8 Hz), 7.59 (s, 1H), 7.63-7.75 (m, 2H), 8.50 (s, 1H), 8.62 (m, 2H).
EXAMPLE 205 Synthesis of 4-[N-(4-metoxyphenyl)-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]-1-[[2-(3,4-dimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00448
4-[N-(4-Methoxyphenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine dihydrochloride (139 mg, obtained in the Preparation Example 98) and 4-chloromethyl-2-(3,4-dimethoxyphenyl)pyridine (80 mg, obtained in the Preparation Example 197) were condensed in the same manner described in the Example 9 to give the title compound as a trihydrochloride.
Yield: 139 mg (67%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.70-1.95 (m, 4H), 2.05-2.20 (m, 2H), 2.90-3.05 (m, 2H), 3.45-3.60 (m, 3H), 3.73 (s, 3H), 3.88 (s, 3H), 3.89 (s, 6H), 3.94 (s, 3H), 4.00 (s, 3H), 4.46 (s, 2H), 6.65 (s, 2H), 6.74-6.82 (m, 4H), 6.94 (d, 1H, J=8.3 Hz), 7.15 (br, 1H), 7.52 (br, 1H), 7.58-7.71 (m, 3H), 8.50 (s, 1H), 8.57 (d, 1H, J=5.2 Hz), 8.62 (br, 1H).
EXAMPLE 206 Synthesis of 4-[N-(4-fluorophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]-1-[[2-(3-methoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00449
4-[N-(4-Fluorophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine dihydrochloride (135 mg, obtained in the Preparation Example 183) and 4-chloromethyl-2-(3-methoxyphenyl)pyridine (70 mg, obtained in the Preparation Example 195) were condensed in the same manner described in the Example 9 to give the title compound as a trihydrochloride.
Yield: 178 mg (92%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.73-1.95 (m, 4H), 2.10-2.25 (m, 2H), 2.93-3.05 (m, 2H), 3.57 (s, 2H), 3.64 (br, 1H), 3.88 (s, 3H), 3.89 (s, 9H), 4.51 (s, 2H), 6.66 (s, 2H), 6.70-6.76 (m, 2H), 6.90 (t, 2H, J=8.3 Hz), 6.96 (d, 1H, J=8.3 Hz), 7.21 (br, 1H), 7.38 (t, 1H, J=8.0 Hz), 7.54 (d, 1H, J=7.8 Hz), 7.58 (s, 1H), 7.65 (s, 1H), 7.74 (br, 1H), 8.50 (s, 1H), 8.61 (d, 1H, J=5.1 Hz), 8.65 (br, 1H).
EXAMPLE 207 Synthesis of 4-[N-(4-fluorophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]-1-[[2-(3,4-dimethoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00450
4-[N-(4-Fluorophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine dihydrochloride (135 mg, obtained in the Preparation Example 183) and 4-chloromethyl-2-(3,4-dimethoxyphenyl)pyridine (80 mg, obtained in the Preparation Example 197) were condensed in the same manner described in the Example 9 to give the title compound as a trihydrochloride.
Yield: 195 mg (96%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.70-1.95 (m, 4H), 2.10-2.24 (m, 2H), 2.94-3.09 (m, 2H), 3.57 (s, 2H), 3.64 (br, 1H), 3.88 (s, 3H), 3.89 (s, 6H), 3.94 (s, 3H), 4.00 (s, 3H), 4.51 (s, 2H), 6.65 (s, 2H), 6.69-6.78 (m, 2H), 6.86-6.97 (m, 3H), 7.16 (d, 1H, J=4.9 Hz), 7.51 (d, 1H, J=8.5 Hz), 7.60-7.70 (m, 3H), 8.50 (s, 1H), 8.58 (d, 1H, J=4.9 Hz), 8.65 (s, 1H).
EXAMPLE 208 Synthesis of 4-[N-(3,4-difluorophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]-1-[[2-(3-methoxyphenyl)pyridin-4-yl]methyl]piperidine trihydrochloride
Figure US06867221-20050315-C00451
4-[N-(3,4-Difluorophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine dihydrochloride (160 mg, obtained in the Preparation Example 176) and 4-chloromethyl-2-(3-methoxyphenyl)pyridine (80 mg, obtained in the Preparation Example 195) were condensed in the same manner described in the Example 9 to give the title compound as a trihydrochloride.
Yield: 130 mg (57%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.73-1.90 (m, 4H), 2.01-2.24 (m, 2H), 2.92-3.05 (m, 2H), 3.57 (s, 2H), 3.67 (br, 1H), 3.88 (s, 3H), 3.89 (s, 3H), 3.90 (s,6H), 4.52 (s, 2H), 6.36-6.42 (m, 1H), 6.50-6.58 (m, 1H), 6.67 (s, 2H), 6.93-7.01 (m, 2H), 7.20 (br, 1H), 7.38 (t, 1H, J=7.8 Hz), 7.52-7.62 (m, 2H), 7.62-7.72 (m, 2H), 8.48 (br, 1H), 8.61 (br, 1H), 8.66 (d, 1H, J=2.0 Hz).
EXAMPLE 209 Synthesis of 1-[[2-(3-methoxyphenyl)pyridin-4-yl]methyl]-4-[N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]-N-(4-methylthiophenyl)amino]piperidine
Figure US06867221-20050315-C00452
4-[N-(4-Metythiophenyl)-N-[[3-(3,4,5-trimethoxyphenyl)pyridin-5-yl]methyl]amino]piperidine dihydrochloride (121 mg, obtained in the Preparation Example 143) and 4-chloromethyl-2-(4-methoxyphenyl)pyridine (55 mg, obtained in the Preparation Example 195) were condensed in the same manner described in the Example 9 to give the title compound.
Yield: 71 mg (44%). 1H-NMR (400 MHz, measured as a free base, CDCl3) δ: 1.72-1.83 (m, 4H), 2.12-2.20 (m, 2H), 2.37 (s, 3H), 2.97 (d, 2H, J=10.8 Hz), 3.56 (s, 2H), 3.75-3.81 (m, 1H), 3.86 (s, 3H), 3.87 (s, 6H), 4.54 (s, 2H), 6.64-6.69 (m, 3H), 6.94 (dd, 1H, J=7.8 Hz, 1.9 Hz), 7.17-7.26 (m, 4H), 7.35 (t, 1H, J=7.8 Hz), 7.51-7.66 (m, 4H), 8.47 (s, 1H), 8.59 (d, 1H, J=4.6 Hz), 8.63 (s, 1H).
Test Example 1 Inhibitory Effect on Cell Adhesion
The test was conducted by reference to the method by Ross et al. (J. Biol. Chem., 267, 8537-8543 (1992)). More specifically, after human umbilical venous endothelial cells (HUVEC) were cultured on a 48-well plate to confluent growth, TNFα was added thereto. Upon elapsed time of 5 hours after the addition, U937, which was a human monocytic/histocytic cell fluorescence-labeled with PKH2 (product of Sigma-Aldrich Co., Ltd.), was added in a proportion of 1×106 cells per well. After the plate was left at rest at room temperature for 1 hour, unadhered U937 was washed out and lysed in 1% Triton X-100 to measure a remaining fluorescence intensity (excitation wavelength: 485 nm; measuring wavelength: 530 nm). HUVEC and U937 were cultured in EGM-2 (product of Sanko Junyaku K. K.) and 10% FCS-containing RPMI1640, respectively. Each test agent was added to HUVEC upon the addition of TNFα and to U937 24 hours prior to the cell adhesion test. The inhibitory activity was calculated out as IC50 value after inhibitory ratio at each concentration of test compounds was determined. The inhibitory ratio was calculated according to the equation [(C−B)/(A−B)×100 (%)], wherein A is the number of U937 cells adhered to HUVEC stimulated by TNFα when no test agent was added, B is the number of U937 cells adhered to HUVEC not stimulated by TNFα when no test agent was added, and C is the number of U937 cells adhered to HUVEC stimulated by TNFα when the test agent was added. The results are shown in Table 1. As control compounds, Test Compound 1 described in Japanese Patent Application Laid-Open No. 9-143075 and dilazep described in Japanese Patent Application Laid-Open No. 11-92382 were simultaneously evaluated.
TABLE 1
Example IC50 (μM)
3 0.3
5 0.2
7 0.3
10 0.04
13 0.03
16 0.3
19 0.3
23 0.03
29 0.03
36 0.2
40 0.2
42 0.07
67 0.09
88 0.07
89 0.09
111 0.08
157 0.09
Test compound 1 10
Dilazep >10
As mentioned above, the compound of the present invention is characterized in that the cyclic amine has two phenyl-pyridyl or biphenyl groups, or phenyl-pyridyl and biphenyl groups. The inhibitory effect on cell adhesion of the cyclic amine compound having pyridyl groups at the both ends thereof obtained in Preparation Example 91 was examined similar to the above procedure. As the result, the compound was inactive even at a concentration as high as 10 μM.
Specific formulation examples will hereinafter be described.
EXAMPLE 210 Capsule Preparation
Compound obtained by Example 13 30 mg
Microcrystalline cellulose 30 mg
Lactose 57 mg
Magnesium stearate  3 mg
Total amount  120 mg. 
The above ingredients were mixed in accordance with a method known per se in the art and then charged in capsules to obtain capsule preparations.
EXAMPLE 211 Tablet Preparation
Compound obtained by Example 13 30 mg
Starch 44 mg
Starch (for glue) 5.6 mg 
Magnesium stearate 0.4 mg 
Calcium carboxymethyl cellulose 20 mg
Total amount  100 mg. 
The above ingredients were mixed in accordance with a method known per se in the art to obtain tablet preparations.
EXAMPLE 212 Injection Preparation
Compound obtained by Example 13 (100 mg) and sodium chloride (900 mg) were dissolved in distilled water (about 80 mL) for injection, and distilled water for injection was added to the resultant solution to 100 mL in total. This diluted solution was sterilized by filtration and then subdivided and charged into 10 ampoules, and the ampoules were sealed to obtain injection preparations.
As described above, the compounds (1) according to the present invention have inhibitory effects on both cell adhesion and cell infiltration and are useful as medicines for prevention or treatment of allergy, asthma, rheumatism, arteriosclerosis, inflammatory, Sjogren's syndrome, etc.
Obviously, numerous modifications of the above teachings are apparent to those skilled in the art. Therefore, within the scope of the appended claims the invention may be practiced otherwise than as specifically described herein.

Claims (18)

1. A cyclic amine compound represented by the following general formula (1):
Figure US06867221-20050315-C00453
wherein,
R1, R2 and R3 each independently represent a hydrogen atom, a halogen atom, or a hydroxy, alkyl, halogen-substituted alkyl, alkoxy, alkylthio, carboxyl, alkoxycarbonyl or alkanoyl group;
W1 and W2 each independently represent N or CH;
X represents NR4, CONR4 or NR4CO, wherein R4 represents substituted aryl, substituted heteroaryl, substituted aralkyl, or substituted heteroaralkyl group, each substituted with 1 to 3 groups selected from alkylsulfinyl and alkylsulfonyl; and
l, m and n are a number of 0 or 1;
or a salt thereof or a hydrate thereof.
2. The compound according to claim 1, wherein R1, R2 and R3 each independently represent a hydrogen atom, a halogen atom, or a hydroxy, C1-C8 alkyl, halogen-substituted C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylthio, carboxyl, C1-C6 alkoxycarbonyl or C1-C6 alkanoyl group.
3. The compound according to claim 1, wherein R4 represents a substituted C6-C14 aryl group, a substituted 5- or 6-membered ring heteroaryl group containing 1 to 4 nitrogen atoms, a substituted C6-C14 aryl-C1-C6 alkyl group, or a substituted 5- or 6-membered ring, 1 to 4 nitrogen atoms-containing heteroaryl-C1-C6 alkyl group.
4. The compound according to claim 1, wherein X represents NR4, and R4 represents a substituted C6-C14 aryl group or a substituted 5- or 6-membered ring heteroaryl group containing 1 to 4 nitrogen atoms in the ring.
5. The compound according to claim 4, wherein W2 represents N.
6. A pharmaceutical composition which comprises as an active ingredient a cyclic amine compound represented by the following general formula (1):
Figure US06867221-20050315-C00454
wherein,
R1, R2 and R3 each independently represent a hydrogen atom, a halogen atom, or a hydroxy, alkyl, halogen-substituted alkyl, alkoxy, alkylthio, carboxyl, alkoxycarbonyl or alkanoyl group;
W1 and W2 each independently represent N or CH;
X represents NR4, CONR4 or NR4CO, wherein R4 represents substituted aryl, substituted heteroaryl substituted aralkyl, or substituted heteroaralkyl group, each substituted with 1 to 3 groups selected from alkylsulfinyl and alkylsulfonyl; and
l, m and n are a number of 0 or 1; or
a salt thereof or a hydrate thereof;
and a pharmaceutical acceptable carrier.
7. The pharmaceutical composition according to claim 6, wherein R1, R2 and R3 each independently represent a hydrogen atom, a halogen atom, or a hydroxy, C1-C8 alkyl, halogen-substituted C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylthio, carboxyl, C1-C6 alkoxycarbonyl or C1-C6 alkanoyl group.
8. The pharmaceutical composition according to claim 6, wherein R4 represents a substituted C6-C14 aryl group, a substituted 5- or 6-membered ring heteroaryl group containing 1 to 4 nitrogen atoms, a substituted C6-C14 aryl-C1-C6 alkyl group, or a substituted 5- or 6-membered ring, 1 to 4 nitrogen atoms-containing heteroaryl-C1-C6 alkyl group.
9. The pharmaceutical composition according to claim 6, wherein X represents NR4, and R4 represents a substituted C6-C14 aryl group or a substituted 5- or 6-membered ring heteroaryl group containing 1 to 4 nitrogen atoms in the ring.
10. The pharmaceutical composition according to claim 9, wherein W2 represent N.
11. The pharmaceutical composition according to claim 6 comprising said active ingredient in an amount effective for treating a disease caused by cell adhesion and/or cell infiltration.
12. The pharmaceutical composition according to claim 11, wherein said disease is selected from allergy, asthma, inflammation, rheumatic disease, arteriosclerosis and Sjogren's syndrome.
13. A method for treating a disease caused by cell adhesion and/or cell infiltration, which comprises administering an effective amount of a cyclic amine compound represented by the following general formula (1):
Figure US06867221-20050315-C00455
wherein,
R1, R2 and R3 each independently represent a hydrogen atom, a halogen atom, or a hydroxy, alkyl, halogen-substituted alkyl, alkoxy, alkylthio, carboxyl, alkoxycarbonyl or alkanoyl group;
W1 and W2 each independently represent N or CH;
X represents NR4, CONR4 or NR4CO, wherein R4 represents substituted aryl, substituted heteroaryl substituted aralkyl, or substituted heteroaralkyl group, each substituted with 1 to 3 groups selected from alkylsulfinyl and alkylsulfonyl; and
l, m and n area number of 0 or 1; or
a salt thereof or a hydrate thereof, to a patient who requires such treatment.
14. The method according to claim 13, wherein R1, R2 and R3 each independently represent a hydrogen atom, a halogen atom, or a hydroxy, C1-C8 alkyl, halogen-substituted C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylthio, carboxyl, C1-C6 alkoxycarbonyl or C1-C6 alkanoyl group.
15. The method according to claim 13, wherein R4 represents a substituted C6-C14 aryl group, a substituted 5- or 6-membered ring heteroaryl group containing 1 to 4 nitrogen atoms, a substituted C6-C14 aryl-C1-C6 alkyl group, or a substituted 5- or 6-membered ring, 1 to 4 nitrogen atoms-containing heteroaryl-C1-C6 alkyl group.
16. The method according to claim 13, wherein X represents NR4, and R4 represents a substituted C6-C14 aryl group or a substituted 5- or 6-membered ring heteroaryl group containing 1 to 4 nitrogen atoms in the ring.
17. The method according to claim 16, wherein W2 represnts N.
18. The method according to claim 13, wherein said disease is selected from allergy, asthma, inflammation, rheumatic disease, arteriosclerosis and Sjogren's syndrome.
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US20050176764A1 (en) * 2002-04-12 2005-08-11 Kowa Co., Ltd Medicine for treating cancer
US20060040986A1 (en) * 2002-12-06 2006-02-23 Kowa Co., Ltd. Erythropoietin production accelerator
US20090143430A1 (en) * 2002-12-06 2009-06-04 Kowa Co., Ltd. Erythropoietin production accelerator
US20070043078A1 (en) * 2003-10-10 2007-02-22 Kowa Co., Ltd. Angiogenesis inhibitor
US20080214614A1 (en) * 2006-12-18 2008-09-04 Lampe John W Cytoskeletal active rho kinase inhibitor compounds, composition and use
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